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64Cu-Labeled Inhibitors of Prostate-Specific Membrane Antigen for PET Imaging of Prostate Cancer

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† Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, Maryland 21287, United States
‡ Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15219, United States
*For S.R.B.: phone, 410-955-8697; fax, 410-614-3147; E-mail, [email protected]; address, Johns Hopkins Medical Institutions, 1550 Orleans Street, 4M07 CRB II, Baltimore, Maryland 21231, United States.
*For M.G.P.: phone, 410-955-2789; fax, 443-817-0990; E-mail, [email protected]; address, Johns Hopkins Medical Institutions, 1550 Orleans Street, 492 CRB II, Baltimore, Maryland 21231, United States.
Cite this: J. Med. Chem. 2014, 57, 6, 2657–2669
Publication Date (Web):February 17, 2014
https://doi.org/10.1021/jm401921j

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Abstract

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Prostate-specific membrane antigen (PSMA) is a well-recognized target for identification and therapy of a variety of cancers. Here we report five 64Cu-labeled inhibitors of PSMA, [64Cu]3–7, which are based on the lysine–glutamate urea scaffold and utilize a variety of macrocyclic chelators, namely NOTA(3), PCTA(4), Oxo-DO3A(5), CB-TE2A(6), and DOTA(7), in an effort to determine which provides the most suitable pharmacokinetics for in vivo PET imaging. [64Cu]3–7 were prepared in high radiochemical yield (60–90%) and purity (>95%). Positron emission tomography (PET) imaging studies of [64Cu]3–7 revealed specific accumulation in PSMA-expressing xenografts (PSMA+ PC3 PIP) relative to isogenic control tumor (PSMA– PC3 flu) and background tissue. The favorable kinetics and high image contrast provided by CB-TE2A chelated [64Cu]6 suggest it as the most promising among the candidates tested. That could be due to the higher stability of [64Cu]CB-TE2A as compared with [64Cu]NOTA, [64Cu]PCTA, [64Cu]Oxo-DO3A, and [64Cu]DOTA chelates in vivo.

Introduction

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The prostate-specific membrane antigen (PSMA) is emerging as an attractive target for addressing cancer, whether for diagnosis or therapy, due to its restricted expression within normal tissue, (1) its elevated expression in the epithelium of prostate tumors, and within the neovasculature of most solid tumors tested. (2) With respect to prostate cancer, elevated expression of PSMA is associated with metastasis, (3) castrate resistance, (4, 5) and progression. (6) PSMA has also been used to guide antibody–drug conjugates and nanoparticles to PSMA-expressing tissues, including for human studies, some of which do not involve prostate cancer. (7-11) Radiohalogenated, urea-based, low-molecular-weight inhibitors of PSMA have recently been explored to image expression of PSMA in prostate tumor xenografts (12, 13) as well as in clinical studies. (14-16) Radiometals, including 99mTc, (17-23)111In, (27-29)64Cu, (30)86Y, (31) and 89Zr, (32, 33) have also recently been implemented for imaging PSMA, in part to leverage the longer physical half-life of these nuclides, which will be necessary for tracking large peptides, aptamers, minibodies, antibodies, and nanoparticles. To enable targeting agents to bind with high affinity to PSMA, a spacer of approximately 20 Å is generally employed between the PSMA-targeting group and the metal chelator. (21) Moreover, we have shown that the chelating moiety has a significant effect on the pharmacokinetics of this class of low-molecular-weight PSMA-based imaging agents when radiolabeled with 99mTc. (34) The search for small-molecule, functionalized affinity agents for PSMA that have longer retention and superior pharmacokinetics properties for imaging and therapeutic applications is ongoing.
64Cu-Labeled molecules are promising imaging agents for positron emission tomography (PET) due to the favorable nuclear characteristics of the isotope (t1/2 = 12.7 h, β+ 17.4%, Emax = 0.656 MeV, β– 39%, Emax = 0.573 MeV) and its availability in high specific activity. (35) The longer physical half-life of 64Cu compared to 11C (t1/2 = 20 min) and 18F (t1/2 = 110 min) enables imaging at delayed time points, which allows sufficient time for clearance from background tissues, resulting in increased image contrast, particularly for targeting agents that demonstrate long circulation times such as antibodies and nanoparticles. Moreover, 64Cu-based PET radiotracers have demonstrated efficacy for radioimmunotherapy (36) comparable to that for the strictly therapeutic radionuclide, 67Cu (t1/2 = 61.5 h, β– 100%, Emax = 0.121 MeV). (37) Accordingly, 64Cu could be used for imaging and therapy concurrently. (38) In vivo stability of 64Cu-labeled targeted biomolecules depends on the stability of the corresponding Cu(II)-chelated coordination complex employed. (39-41) Numerous bifunctional chelating agents have been developed to form stable 64Cu(II) complexes based on well-developed copper coordination chemistry (42) and have been used to functionalize small molecules, (43, 44) peptides, (45-48) aptamers, (49) and antibodies. (50, 51) Acyclic and macrocyclic polyamines tend to have limited stability in vivo with respect to chelation of copper(II). (52, 53) Complexes of copper based on macrocyclic polyamino carboxylates, such as copper chelates of 1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N‴-tetraacetic acid (TETA) and 1,4,7,10-tetraazacyclodoadecane-N,N′,N″,N‴-tetraacetic acid (DOTA), have greater kinetic inertness than acyclic analogues, although this has not eliminated transchelation. (53, 54) The cross-bridged tetraamine bicyclic polyaminocarboxylates, specifically 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A), provide an improvement over the monocyclic counterparts. The superior kinetic stability of the copper(II) cross-bridged complexes relative to DOTA and TETA analogues (55-57) is due to the rigidity of the cross-bridge system. Derivatives of the polyaminocarboxylate NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) are encouraging both because of the convenience of radiolabeling with 64Cu(II) and the lack of subsequent transmetalation in vivo. (46, 47, 58)
Here we study the effect of various chelators for labeling 64Cu on PSMA-targeted ureas with respect to pharmacokinetics for imaging prostate tumor xenografts in vivo. Although these low-molecular-weight compounds may clear relatively rapidly from nontarget sites, that is not always the case, and increasingly, larger PSMA-specific probes with slower kinetics are sometimes used as diagnostic and/or therapeutic probes for PSMA, requiring the longer physical half-life of 64Cu. Optimization of the chelator for radiolabeling with 64Cu is an important initial step in its implementation for imaging species that target PSMA. We investigated the in vitro binding affinity, mouse biodistribution, and prostate tumor xenograft uptake of five 64Cu-labeled PSMA inhibitors. To do that, we prepared urea-based PSMA inhibitors that utilize the Lys-Glu urea motif and conjugated them with five different macrocyclic chelating agents, NOTA, CB-TE2A, 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene)-3,6,9-triacetic acid (PCTA), oxa-4,7,1-tetraazacyclododecane-4,7,10-triacetic acid (oxo-DO3A), (59) and DOTA. Each conjugate was labeled with 63/65Cu/64Cu. Imaging and biodistribution studies in NOD/SCID mice harboring prostate tumor xenografts demonstrated that both 64Cu-labeled NOTA- and CB-TE2A-conjugated radiotracers exhibited favorable pharmacokinetics over the PCTA, oxo-DO3A, and DOTA-conjugated compounds. Between the NOTA- and CB-TE2A-chelated compounds, the 64Cu-labeled CB-TE2A conjugated [64Cu]6B exhibited superior tumor-to-background ratios and is the most promising agent from the series.

Results

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Chemical and Radiochemical Syntheses

Macrocyclic Chelator-Conjugated PSMA Inhibitors

We have synthesized two different types of ligands as shown in Figure 1 using Lys-Glu urea as the targeting moiety. For ligands 3–5 we used a Lys-suberate linker (21) and conjugated the linker with commercially available chelating agents, NOTA-Bn-SCN, PCTA-Bn-SCN, and oxo-DOTA-Bn-SCN via thiourea bond formation. For those three bifunctional chelators, the macrocyclic backbone was functionalized to carry a benzyl isocyanate for conjugation with an amine function. Copper(II) compounds for 3–5 are predicted to demonstrate distorted octahedron geometry. (41) Because NOTA is a hexadentate N3O3 chelator, [64Cu(II)]3 is expected to carry a negative charge. On the other hand, both PCTA (N4O3) and oxo-DOTA (N3O4) are heptadentate macrocycles and likely form neutral compounds with one pendant acetate arm after complexation. (35, 41) The Lys-suberate linker was extended using two phenylalanine residues to prepare 6 and 7 containing CB-TE2A and DOTA, respectively, as chelating agents. The purpose of attaching those two phenylalanine residues to the linker of 6 and 7 is mainly to compensate for the lipophilicity of the phenylthiourea moiety of compounds 3–5. (22, 24-26) Note that one of the pendant acetate arms of the CB-TE2A and DOTA chelators has been modified to attach the PSMA targeting moiety via amide bond formation to produce 6 and 7, respectively. [64Cu]CB-TE2A forms a positively charged radiotracer when conjugated to a biomolecule, whereas DOTA-conjugated [64Cu]7 is expected to carry one pendant acetate, providing an overall neutral compound.

Figure 1

Figure 1. Proposed structures of 64Cu-labeled inhibitors of PSMA.

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Syntheses of PSMA targeting ligands 3, 4, and 5 are shown in Scheme 1. Compounds 1 and 2 were prepared as previously reported. (28) Compound 2 was conjugated with commercially available NOTA-Bn-SCN, PCTA-Bn-SCN, and oxo-DOTA-Bn-SCN in DMSO in the presence of diisopropylethylamine (DIEA) at 40 °C for 4 h, to give 3, 4, and 5 in ∼30–40% yield, respectively, after purification by high-performance liquid chromatography (HPLC). Synthesis of CB-TE2A-conjugated ligand 6 was performed using standard fluorenylmethoxycarbonyl (Fmoc) solid phase peptide synthesis (SPPS), starting from Fmoc-Lys(Boc)-Wang resin according to Scheme 2. After two phenylalanine residues were coupled with the resin bound lysine, CB-TE2A was conjugated at the N-terminal of the second phenylalanine residue, after which the compound was cleaved from the resin by a 1:1 mixture of TFA/CH2Cl2 to produce 8 in moderate yield (∼20%). The free ε-amine of lysine of 8 was then conjugated with 1 (28) to produce 6. DOTA-conjugated 7 was prepared according to our previous report. (26) NMR and mass spectrometry (MS) were used to confirm the identity of newly synthesize compounds. Copper (63/65Cu) complexes were prepared by incubating conjugates 3–7 with an aqueous solution of Cu(NO3)2 at 95 °C as shown in Schemes 1–2. The mass spectra of the copper-labeled compounds showed the expected isotope distribution pattern for natural copper, which is a mixture of 63Cu (69%) and 65Cu (31%). The stable copper-labeled conjugates were used as authentic reference material for chromatography to identify the corresponding 64Cu-labeled compounds.

Scheme 1

Scheme 1. Synthesis of [64Cu]3–5
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Scheme 2

Scheme 2. Synthesis of [64Cu]6
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Radiochemistry

The radiolabeling of new PSMA ligands with 64Cu is shown in Schemes 1–2. Briefly, for ligands 3–5 and 7, radiolabeling was performed at pH ∼5.5–6 in acetate buffer at ∼65 °C for 30 min, whereas for ligand 6, radiolabeling was achieved in a boiling water bath (95 °C) for 1 h at pH ∼7.5–8 in acetate buffer. Radiolabeled products were obtained in high yield (>60%, without decay correction) and radiochemical purity (>95%) as determined by HPLC and radio thin-layer chromatography (radio-TLC). Two radiolabeled peaks were observed for [64Cu]4, likely due to the separation of diastereomers as previously reported for this class of bifunctional chelators. (60) On the other hand, free ligand 6 contained two nearly inseparable isomeric peaks by HPLC. Therefore, radiolabeling of 6 was performed using the isomeric mixture to give two HPLC separable products designated [64Cu]6A and [64Cu]6B, isolated in 45% and 35% yield, respectively. We assumed that the presence of an asymmetric center at the Phe residue of the linker moiety adjacent to CB-TE2A was responsible for producing those two diastereomeric compounds. All radioligands were obtained in specific activities ranging from 2.9 to 9.1 GBq/μmol (78–347 mCi/μmol). The Log Poct/w values for the radioligands were determined by octanol–water partition and are shown in Table 1. Surprisingly, [64Cu]6A and [64Cu]6B were found to be more hydrophilic than [64Cu]3 in spite of possessing two Phe residues on the linker and only one carboxylate groups on the chelator backbone.
Table 1. Radiolabeling Yield, Log Po/w, and PSMA Inhibitory Activity
 yield (%)Log Poct/w Ki (nM)
   32.84
[64Cu]3∼65–70–1.17[63/65Cu]36.23
   42.03
[64Cu]4∼70–90–1.42[63/65Cu]410.76
   53.10
[64Cu]5∼75–85–1.56[63/65Cu]55.47
   60.19
[64Cu]6A∼40–45–2.68[63/65Cu]6A3.98
[64Cu]6B∼30–35–2.31[63/65Cu]6B4.65
   711.07
[64Cu]7∼65–70ND[63/65Cu ]713.26

In Vitro Binding

Ligands and the corresponding stable metal-labeled compounds demonstrated high binding affinity to PSMA, with Ki values ranging from 0.19 to 13.26 nM (Table 1). The known, high-affinity PSMA inhibitor ZJ43 was used as a reference ligand (Supporting Information Figure S1) and exhibits a Ki of 4.3 nM. (61) The low nanomolar affinities displayed by these five new copper compounds are similar to the affinities of the majority PSMA-targeted imaging agents we have synthesized to date. (21, 28)

Small Animal PET-CT Imaging

Whole body PET-CT images were obtained for [64Cu]3–7 in intact male severe combined immunodeficient (SCID) mice (Figures 2–4) bearing PSMA+ PC3 PIP and PSMA– PC3 flu xenografts in opposite, upper flanks. Pharmacokinetics derived from the images were used to determine which compound(s) would be further evaluated through ex vivo biodistribution. Irrespective of charge and lipophilicity, all radiotracers, [64Cu]3–7, enabled visualization of PSMA+ PC3 PIP tumor and kidneys (Figure 2). Renal uptake of the radiotracers is partially due to the route of excretion of these agents as well as to specific uptake from the expression of PSMA in mouse proximal renal tubules. (62) Although [64Cu]4, [64Cu]5, and [64Cu]7 demonstrated moderate to high PSMA+ PC3 PIP tumor uptake, they also showed significant accumulation within liver at 2.5 h postinjection (Figure 2), which remained high until 6 h (data not shown). Radioligands [64Cu]5 and [64Cu]7 exhibited significantly higher background uptake, probably related to lower stability of these 64Cu complexes, (58) resulting in trans-chelation of copper to other, endogenous proteins. (56)

Figure 2

Figure 2. Whole body PET-CT imaging of PSMA+ PC3 PIP and PSMA – PC3 flu tumor-bearing mice with compounds [64Cu]3, [64Cu]4, [64Cu]5, [64Cu]6B, and [64Cu]7 at 2.5 h postinjection, respectively. Mice were injected with ∼11.1 MBq (∼300 μCi) of radiotracer IV. PIP = PSMA+ PC3 PIP (solid arrow); flu = PSMA– PC3 flu (unfilled arrow); K= kidney; B = bladder; L = left; R = right. All images are decay-corrected and adjusted to the same maximum value.

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PET-CT images acquired at 20 min, 6 and 28 h postinjection of [64Cu]3 (Figure 3) (n = 2) showed clear uptake in PSMA+ PC3 PIP tumor. At 20 min and 6 h postinjection, the most visible tissues were PSMA+ PC3 PIP tumor and kidneys, with some accumulation of radioactivity observed in liver and urinary bladder. Radioactivity in liver and kidneys cleared significantly by 28 h.

Figure 3

Figure 3. Whole body PET-CT imaging of PC3 PIP and PC3 flu tumor bearing mice with [64Cu]3 at 20 min (left), 6 h (middle), 28 h (right). Abdominal radioactivity is primarily due to uptake within kidneys and bladder. PIP = PC3 PSMA+ PIP (solid arrow); flu = PC3 PSMA– flu (unfilled arrow); K= kidney; L = left; R = right, B = bladder. All images are decay-corrected and adjusted to the same maximum value.

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Compounds [64Cu]6A and [64Cu]6B exhibited high radiotracer concentration both within PSMA+ PC3 PIP tumor and kidneys, similar to the distribution profile observed with [64Cu]3. Significantly, both CB-TE2A conjugated diastereomers [64Cu]6A and [64Cu]6B exhibited similar PET imaging profiles as shown in Figure 4. Both compounds showed low liver uptake as early as 20 min after the injection. Consequently, clear delineation of tumor was achieved even at early time points. By 2.5 h postinjection, radioactivity was largely cleared from kidneys for both isomers, producing clear target-to-background contrast for these radiotracers. As a further test of binding specificity, we imaged animals administered [64Cu]6B after pretreating them with 50 mg/kg of ZJ43 30 min prior to radiotracer. (61) ZJ43 proved capable of blocking binding of [64Cu]6B (Supporting Information Figure S2), not only within the tumor but also within the renal cortex, confirming that uptake observed in these tissues is PSMA-mediated. (62)

Figure 4

Figure 4. Whole body PET-CT imaging of PC3 PIP and PC3 flu tumor bearing mice with [64Cu]6A (top row) and [64Cu]6B (bottom row) at 20 min, 2.5 h, 12 and 22 h postinjection. Abdominal radioactivity is primarily due to uptake within kidneys and bladder. PIP = PC3 PSMA+ PIP (solid arrow); flu = PC3 PSMA− flu (unfilled arrow); K= kidney; L = left; R = right, B = bladder. All images are decay-corrected and adjusted to the same maximum value.

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Biodistribution

On the basis of PET-CT imaging results, [64Cu]3, [64Cu]6A, and [64Cu]6B were further assessed in a biodistribution assays using the same isogenic human prostate cancer PSMA+ PC3 PIP and PSMA– PC3 flu tumor models (n = 4). Tables 2 and 3 show the pharmacokinetics in percentage of injected dose per gram of tissue (% ID/g) in selected organs for [64Cu]3 and [64Cu]6A at 30 min, 1 h, 2 h, and at 4 or 5 h postinjection, while Table 4 shows the % ID/g at the optimized time point of 2 h for [64Cu]3, [64Cu]4, [64Cu]6A, and[64Cu]6B. All compounds exhibited clear PSMA-dependent binding in PSMA+ PC3 PIP tumor xenografts, with [64Cu]3 demonstrating high tumor uptake as early as 30 min postinjection (33.78 ± 9.68% ID/g), peaking at 2 h (38.51 ± 5.68% ID/g) (Table 2), with extended retention of radioactivity up to 4 h postinjection (20.64 ± 5.06% ID/g). PSMA+ PC3 PIP to PSMA– PC3 flu tumor uptake ratios were 14.03 ± 3.71 and 23.50 ± 4.65 at 30 min at 4 h, respectively. The distribution within normal organs and tissues was also favorable, with low blood and normal tissue uptake and rapid clearance. The highest nonspecific uptake observed was in the liver (7.37 ± 0.40% ID/g) and spleen (28.02 ± 5.82% ID/g) at 30 min postinjection. However, those values decreased to 4.18 ± 1.61% ID/g and 4.72 ± 1.49% ID/g, respectively, by 4 h. Kidney uptake was expectedly high and peaked at 195.44 ± 29.82% ID/g at 30 min and decreased to 108.05 ± 20.50% ID/g by 4 h.
Table 2. Tissue Biodistribution for [64Cu]3 in Tumor-Bearing Micea
 0.5 h1 h2 h4 h
blood2.37 ± 0.901.12 ± 0.210.82 ± 0.200.45 ± 0.20
heart1.78 ± 0.411.39 ± 0.241.11 ± 0.130.71 ± 0.26
lung6.40 ± 0.595.99 ± 0.704.51 ± 0.972.49 ± 0.99
liver7.37 ± 0.407.50 ± 1.436.44 ± 0.834.18 ± 1.61
spleen28.02 ± 5.8227.58 ± 10.0512.33 ± 6.324.72 ± 1.49
fat1.78 ± 0.311.43 ± 0.380.76 ± 0.340.65 ± 0.75
kidney195.44 ± 29.82233.39 ± 22.76199.69 ± 48.44108.05 ± 20.50
muscle0.57 ± 0.320.60 ± 0.140.34 ± 0.120.21 ± 0.10
small intestine4.60 ± 1.425.58 ± 1.433.68 ± 0.412.44 ± 1.30
large intestine4.51 ± 1.646.01 ± 2.543.80 ± 1.672.42 ± 1.19
bladder5.65 ± 2.772.48 ± 0.4213.33 ± 8.351.70 ± 0.97
PC-3 PIP33.79 ± 9.6829.11 ± 3.0238.51 ± 5.6820.64 ± 5.06
PC-3 flu2.40 ± 0.172.02 ± 0.181.92 ± 0.231.04 ± 0.37
PIP:flu14.03 ± 3.7114.37 ± 0.4319.96 ± 0.8123.50 ± 4.65
PIP:blood15.11 ± 5.3826.64 ± 5.1248.75 ± 10.2750.01 ± 15.54
a

Values expressed are in % ID/g ± standard deviation; n = 4 for all tissues.

Table 3 shows the organ-related % ID/g of uptake for [64Cu]6B. Similar to [64Cu]3, [64Cu]6B showed the highest PSMA-dependent tumor uptake with 29.50 ± 8.10% ID/g at 1 h postinjection. Tumor uptake remained high, decreasing to 18.69 ± 2.88% ID/g at 5 h. The PSMA+ PC3 PIP to PSMA– PC3 flu ratios were 19.36 ± 3.98 at 30 min, 79.40 ± 15.83 at 2 h, and 146.79 ± 32.20 at 5 h. The PSMA+ PC3 PIP tumor-to-muscle ratio reached a maximum value of 436.14 ± 202.71 at 5 h, nearly 3-fold higher than those observed with [64Cu]3. Renal uptake for [64Cu]6B was highest at 30 min at 256.11 ± 75.72% ID/g, much higher than that seen for [64Cu]3, however, it cleared much more rapidly, decreasing to 3.54 ± 0.04% ID/g by 5h. Nontarget organs, such as blood, heart, liver, spleen, stomach, and pancreas, showed lower uptake (∼2% ID/g at 1 h) and much faster clearance than for [64Cu]3 and decreased to below 1% ID/g by 5 h.
Table 3. Tissue Biodistribution for [64Cu]6B in Tumor-Bearing Micea
 0.5 h1 h2 h5 h
blood2.50 ± 1.080.64 ± 0.240.26 ± 0.130.06 ± 0.05
heart0.92 ± 0.270.32 ± 0.080.13 ± 0.050.06 ± 0.01
lung2.70 ± 0.730.83 ± 0.110.45 ± 0.210.15 ± 0.01
liver0.73 ± 0.170.42 ± 0.040.30 ± 0.060.21 ± 0.03
stomach1.02 ± 0.470.48 ± 0.280.25 ± 0.060.10 ± 0.03
pancreas0.90 ± 0.230.31 ± 0.190.13 ± 0.050.05 ± 0.04
spleen5.80 ± 2.612.14 ± 0.580.65 ± 0.150.25 ± 0.07
fat0.87 ± 0.150.87 ± 1.320.19 ± 0.100.05 ± 0.05
kidney256.11 ± 75.72148.60 ± 48.4165.39 ± 21.163.54 ± 0.04
muscle0.33 ± 0.011.71 ± 2.290.17 ± 0.050.05 ± 0.02
small intestine0.85 ± 0.411.38 ± 1.890.26 ± 0.070.11 ± 0.10
large intestine0.88 ± 0.420.77 ± 0.650.30 ± 0.080.14 ± 0.05
bladder3.99 ± 0.267.06 ± 3.752.21 ± 0.571.43 ± 1.41
PC-3 PIP23.14 ± 2.2029.50 ± 8.1020.46 ± 2.9018.69 ± 2.88
PC-3 flu1.29 ± 0.120.66 ± 0.260.26 ± 0.040.13 ± 0.03
PIP:flu19.36 ± 3.9848.41 ± 14.2579.40 ± 15.83146.79 ± 32.30
PIP:blood9.13 ± 5.2347.47 ± 7.24101.17 ± 6.701123.96 ± 25.83
PIP:muscle69.35 ± 4.2991.30 ± 93.17132.99 ± 43.97436.14 ± 202.71
a

Values expressed are in % ID/g ± standard deviation; n = 4 for all tissues.

Because [64Cu]3, [64Cu]4, and [64Cu]6 demonstrated superior pharmacokinetics to [64Cu]5 and [64Cu]7, a one-time point (2 h) biodistribution study (Table 4) was performed with [64Cu]3, [64Cu]4, and [64Cu]6B. Syntheses and biodistribution studies were performed on the same day, as close to one another as possible to minimize the changes in specific activity of the radiotracer. The biodistribution and imaging data reveal several important points regarding the in vivo properties of these compounds. The NOTA-chelated radiotracers [64Cu]3, PCTA-chelated [64Cu]4, and CB-TE2A-chelated [64Cu]6B showed high uptake in PSMA+ PC3 PIP tumor, highest for [64Cu]4 (24.13 ± 10.06% ID/g). However, [64Cu]4 also exhibited slightly higher nonspecific uptake in PSMA– PC3 flu tumor and other organs, including blood, muscle, heart, liver, and stomach, resulting in lower tumor-to-organ ratios than for [64Cu]3 and [64Cu]6B. In the imaging studies, [64Cu]4 exhibited considerable background radioactivity primarily due to high liver uptake of [64Cu]4. Diastereomers [64Cu]6A and [64Cu]6B, each containing the CB-TE2A chelating agent, possessed similar in vivo properties and exhibited significantly lower normal tissue uptake, including kidney, than either [64Cu]3 or [64Cu]4.
Table 4. Tissue Biodistibistion for [64Cu]3, [64Cu]4, [64Cu]6A, and [64Cu]6B at 2 h Post-Injection in Tumor-Bearing Micea
 [64Cu]3[64Cu]4[64Cu]6A[64Cu]6B
blood1.06 ± 0.291.87 ± 0.630.20 ± 0.030.20 ± 0.07
heart1.48 ± 0.142.71 ± 0.130.26 ± 0.100.35 ± 0.21
lung5.31 ± 0.7410.16 ± 2.291.17 ± 0.610.89 ± 0.15
liver8.63 ± 0.9217.04 ± 1.441.68 ± 0.381.63 ± 0.72
stomach3.88 ± 0.826.37 ± 0.780.62 ± 0.420.62 ± 0.17
pancreas2.22 ± 0.343.51 ± 0.670.46 ± 0.440.80 ± 0.92
spleen13.42 ± 1.189.27 ± 2.280.39 ± 0.300.90 ± 0.23
fat0.76 ± 0.771.18 ± 0.590.27 ± 0.260.05 ± 0.02
kidney125.40 ± 42.47166.57 ± 42.3923.55 ± 8.9624.87 ± 11.26
muscle0.33 ± 0.080.71 ± 0.320.11 ± 0.050.12 ± 0.05
small intestine6.24 ± 1.4610.95 ± 3.700.74 ± 0.320.68 ± 0.13
large intestine10.13 ± 6.8310.10 ± 4.761.49 ± 0.751.28 ± 0.70
bladder12.47 ± 10.3010.56 ± 6.207.98 ± 8.325.92 ± 4.94
PC-3 PIP16.58 ± 3.1524.13 ± 10.0611.10 ± 5.4216.89 ± 5.73
PC-3 flu2.12 ± 0.253.88 ± 0.620.36 ± 0.090.40 ± 0.12
PIP:flu11.00 ± 0.736.22 ± 1.8630.90 ± 7.9241.75 ± 5.54
PIP:blood16.52 ± 5.1412.87 ± 1.8752.41 ± 17.3486.97 ± 15.22
PIP:muscle46.98 ± 19.0538.34 ± 21.6997.31 ± 42.46138.88 ± 30.86
a

Values expressed are in % ID/g ± standard deviation; n = 4 for all tissues.

Discussion

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We have evaluated five 64Cu-labeled PSMA-targeted, urea conjugates using different chelating agents with the aim of optimizing in vivo PET imaging properties of this class of compounds for clinical application. It is generally accepted that the overall biologic profile of radiolabeled ligands is determined not only by receptor-specific binding but also by nonspecific interactions. Such off-target effects rely on the overall physicochemical features of the radiolabeled compound, e.g., molecular weight, charge, lipophilicity, and metabolic stability. The chelator used to attach the radionuclide to the targeting agent plays a key role in establishing those physicochemical features, particularly for agents smaller than antibodies and nanoparticles, namely those of relatively low molecular weight (<1500 Da). Two key findings emerged from this study. First, both NOTA and CB2-TE2A-conjugated radiotracers [64Cu]3 and [64Cu]6 demonstrated significantly higher in vivo stability, as evidenced by their lower liver uptake than the other three radiotracers, [64Cu]4, [64Cu]5, and [64Cu]7, which utilized PCTA, oxo-DOTA, and DOTA, respectively. High liver uptake and slow blood clearance for those latter three radiotracers are indicative of free Cu(II), which is sequestered in liver. (56, 63) Second, liver uptake and blood concentration are much lower at all time points for [64Cu]6A–B compared to [64Cu]3, suggesting higher in vivo stability of CB-TE2A-conjugated [64Cu]6A–B compared to NOTA-conjugated [64Cu]3. That might also be related to the higher hydrophilicity of [64Cu]6A–B compared to [64Cu]3 (Log Po/w = −2.68 for [64Cu]6B compared to −1.17 for [64Cu]3). Low liver uptake of CB-TE2A-chelated [64Cu]6 ligands might also be related their higher stability in forming complexes with Cu(II) and Cu(I), assuming Cu(II) reduction is the primary reason for transchelation, as reported previously. (56) It is worth mentioning that [64Cu]3, which possesses an overall negative charge, exhibited higher kidney and spleen uptake that was similar to that observed for 99mTc-oxo labeled PSMA-targeted compounds. (34)
Both kidney and tumor uptake of [64Cu]6B were specifically blocked by ZJ43, demonstrating PSMA-mediated renal uptake, however, much faster renal clearance of [64Cu]6B was observed compared to clearance from PSMA+ PIP tumor. We and others have seen a similar pattern of faster clearance of radioactivity from PSMA-expressing kidney than PSMA+ PIP tumor, presumably associated with more rapid flow through normally organized renal parenchymal vasculature compared to the relatively disorganized vasculature of the xenograft. (26, 64, 65) As an extension of that particular pharmacokinetic feature, [64Cu]6 exhibited the highest tumor-to-normal tissue ratios in this series of agents and the ratios increased with time, thereby providing high image contrast. Moreover, no bone uptake was observed for [64Cu]6, indicating that this agent may find application for detection of prostate cancer metastases, which are preferentially found in bone.
The imaging and biodistribution results demonstrate higher in vivo stability and renal clearance for CB-TE2A-chelated [64Cu]6 compared to NOTA-chelated [64Cu]3, which appears to be in contradistinction to previous reports that involve similar comparison for agents that target somatostatin receptor and αvβ3 integrin. In those reports [64Cu]NOTA-conjugated radiopeptides provided faster renal clearance than those conjugated with [64Cu]CB-TE2A. (46, 47) Although unclear at this time, this difference between 64Cu-labeled species for targeting of PSMA vs somatostatin receptor or integrin may be associated with other physical properties unique to each system such as binding affinity or capacity for internalization of the cognate ligands. It nevertheless underscores the uniqueness of each system and indicates that one chelator cannot be assumed to outperform another in a new, untested system.
There are several classes of imaging agents available for PET-based molecular imaging of PSMA, including antibodies, (4, 5, 32, 66) antibody fragments, (67) aptamers, (49) and low-molecular-weight PSMA-binding affinity agents. (14, 64) They have widely varying pharmacokinetics, however, each class has shown PSMA-specific binding in preclinical studies. Rockey and colleagues have recently optimized conditions for conjugating 64Cu to a PSMA-targeting aptamer with different chelators, which has shown PSMA-mediated uptake in PSMA+ 22Rv1 prostate tumor cells relative to PSMA– PC3 cells. (49) The radiolabeled monoclonal antibodies [64Cu]DOTA-3/A1214 and [89Zr]DFO-J591 (55) both showed values of approximately 3:1 at 48 h post-injection for PSMA+ to PSMA- tumor. Among the long-lived PET radionuclides, 64Cu and 89Zr, the stability of the [89Zr]DFO complex is limited as shown in several in vitro and in vivo in studies, which is reflected in a bone accumulation ranging from 3 to 15% and assumed to be associated with the nonlinear nature of the desferrioxamine (DFO) chelating agent. (68) More recently, studies in biopsy tissue from patients with prostate cancer and cell lines have demonstrated a correlation between PSMA cell–surface expression and androgen activity using 64Cu-labeled anti-PSMA antibody ([64Cu]J591). (20) ImmunoPET detection of PSMA could provide a path for quantitative monitoring of successful androgen blockade in patients. Low-molecular-weight urea-based agent [64Cu]6 could be an inexpensive alternative for those applications. Furthermore, results obtained with [64Cu]6 suggest that delayed imaging with 64Cu-labeled PSMA-targeted ligands using CB-TE2A can improve the visualization of PSMA+ tumors in vivo anywhere outside of central nervous system and may allow imaging of tumors with lower PSMA expression levels than possible with existing 18F- or 68Ga-labeled PSMA-targeted imaging agents.

Conclusion

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We describe five new low-molecular-weight, urea-based, 64Cu-labeled, PSMA-targeted radiotracers that incorporated well-established chelating agents. All compounds demonstrated high tumor uptake and retention with the choice of chelator having a profound effect on pharmacokinetics. Our data revealed that [64Cu]6, which utilizes the CB-TE2A chelator, demonstrated improved biodistribution with rapid clearance from normal tissues, including kidney, resulting in significantly improved image contrast. Accordingly, [64Cu]6 provides a potentially clinically viable imaging agent for PSMA+ tissues, particularly if delayed imaging, obtainable with a 64Cu-labeled agent, is required.

Experimental Section

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Solvents and chemicals purchased from commercial sources were of analytical grade or better and used without further purification. All 9-fluorenylmethyloxycarbonyl (Fmoc) protected amino acids including the Fmoc-Lys(Boc)-Wang resin, 1-hydroxybenzotriazole monohydrate, and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) were purchased from Chem Impex International Inc. (Wooddale, IL). [64Cu]CuCl2 was purchased from the University of Wisconsin. DOTA-tris(t-butyl ester)-monoacid, p-SCN-Bn-NOTA, p-SCN-Bn-PCTA, and p-SCN-Bn-oxo-DO3A were received from Macrocyclics Inc. (Dallas, TX). Copper(II) chloride, triethylsilane (Et3SiH), diisopropylethylamine (DIEA), and triethylamine (TEA) were purchased from Sigma-Aldrich (St. Louis, MO). All other chemicals were purchased from Thermo Fisher Scientific (Pittsburgh, PA) unless otherwise specified. Analytical thin-layer chromatography (TLC) was performed using Aldrich aluminum-backed 0.2 mm silica gel Z19, 329-1 plates and visualized by ultraviolet light (254 nm), I2, and 1% ninhydrin in EtOH. Flash chromatography was performed using silica gel (MP SiliTech 32-63 D 60 Å) purchased from Bodman (Aston, PA). All in vitro PSMA binding studies and determination of partition coefficient experiments were performed in triplicate to ensure reproducibility. 1H NMR spectra were recorded on a Bruker UltrashieldTM 400 MHz spectrometer. Chemical shifts (δ) are reported in ppm downfield by reference to proton resonances resulting from incomplete deuteration of the NMR solvent. Low resolution ESI mass spectra were obtained on a Bruker Daltonics Esquire 3000 Plus spectrometer. High resolution mass spectra were obtained by the University of Notre Dame Mass Spectrometry and Proteomics Facility, Notre Dame, IN, using ESI either by direct infusion on a Bruker microTOF-II or by LC elution via an ultrahigh pressure Dionex RSLC with C18 column coupled with a Bruker microTOF-Q II.
HPLC purification of compounds 3–7 was performed using a Phenomenex C18 Luna 10 × 250 mm2 column on a Waters 600E Delta LC system with a Waters 486 variable wavelength UV/vis detector, both controlled by Empower software. HPLC was performed using the following methods. Method 1: solvent A (0.1% TFA in water) and solvent B (0.1% TFA in in acetonitrile), flow rate 8 mL/min. The elution gradient was 90% A and 10% B for 0–5 min and 90% A to 0% A and 10% B to 100% B over 6–30 min. Methods 2–5 were isocrati,c with a flow rate 4 mL/min. Method 2: 85% A and 15% B for 0–50 min. Method 3: 82% A and 18% B for 0–40 min. Method 4: 83% A and 17% B for 0–40 min. Method 5: 78% A and 22% B for 0–30 min. Method 6: 80% A and 20% B for 0–30 min, flow rate 1 mL/min, and a Waters Novapak C18 150 × 3.9 mm2 column was used. HPLC purification of [64Cu]3-7 were performed on a Varian Prostar System (Palo Alto, CA), equipped with a Varian ProStar 325 UV–vis variable wavelength detector and a Bioscan Flow-Count in-line radioactivity detector, all controlled by Galaxie software. The specific radioactivity was calculated as the radioactivity eluting at the retention time of product during the preparative HPLC purification divided by the mass corresponding to the area under the curve of the UV absorption. The purity of tested compounds as determined by analytical HPLC with absorbance at 220 nm were >95%.

Synthesis and Characterization of Compounds 1–7

Compounds 1, (28) and 2, (26) and 7 (26) were prepared following our previous reports. Compounds 3–5 were prepared following a general procedure as described for compound 3.

9,16,24-Trioxo-1-thioxo-1-((4-(((S)-1,4,7-tris(carboxymethyl)-1,4,7-triazonan-2-yl)methyl)phenyl)amino)-2,8,17,23,25-pentaazaoctacosane-7,22,26,28-tetracarboxylic Acid, Compound 3

To a solution of 2 (20 mg, 0.33 μmol in 500 μL of DMSO) was added NOTA-Bn-SCN (18.5 mg, 0.33 μmol in 500 μL of DMSO) and DIEA (100 μL), and the solution was kept at 40 °C for 4 h. The reaction mixture was then evaporated to dryness, and the crude residue was dissolved in 2 mL of water and loaded on a prepacked C18 column (5.5 g, Agilent SF10). The product was eluted with 80/20–70/30 H2O (0.1%TFA)/CH3CN (0.1% TFA) solution. The fractions containing the products were combined together and evaporated to dryness to obtain a colorless solid. The solid thus obtained was further purified by HPLC (method 1, retention time, Rt 15.80 min). Yield ∼8 mg (0.076 μmol, ∼23%) after HPLC purification and lyphilization. 1H NMR (DMSO-d6) δ: 8.15 (m, 1H, HNCO(Lys-linker)), 7.75 (m, 1H, HNCO(Lys)), 7.14 (d, 2H, Bz), 6.78 (d, 2H, Bz), 6.34 (m, 2H, NH(CO)NH), 4.40–3.99 (m, 3H, HC(NHCO2(Glu), HC(NHCO2(Lys), HC(NHCO2(Lys)), 3.40–3.30 (m, 7H, NCH2, CHCH2, (NOTA)), 3.21–3.03(m, 16H, (CH2)2(NOTA), H2C-Bz, H2CNH(Lys-linker), H2CNH(Lys)), 2.40–2.09 (m, 6H, H2CCO2(Glu), H2CCO2(linker), H2CCO2(linker)),1.89–1.55 (m, 6H, H2CCH(Glu), H2CCH(Lys-linker), H2CCH(Lys)), 1.55–1.21 (m, 16H, (CH2)2(Lys), (CH2)2(Lys-Linker), (CH2)4(linker)). ESMS m/z: 1054 [M + H]+. HRESI+ MS: calcd for C46H72N9O17S, 1054.4767 [M + H]+; found, 1054.4771.

9,16,24-Trioxo-1-thioxo-1-((4-(((4S)-3,6,9-tris(carboxymethyl)-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(14),12-dien-4-yl)methyl)phenyl)amino)-2,8,17,23,25-pentaazaoctacosane-7,22,26,28-tetracarboxylic Acid, Compound 4

The compound was purified by HPLC (method 1; Rt 15.60 min). Yield ∼12 mg (0.076 μmol, ∼23%) after HPLC purification and lyophilized. 1H NMR (DMSO-d6) δ: 8.14 (m, 1H, HNCO(Lys-linker)), 7.80–7.75 (m, 2H, HNCO(Lys), Py), 7.32 (d, 2H, Py), 7.15 (d, 2H, Bz), 6.78 (d, 2H, Bz), 6.35 (m, 2H, NH(CO)NH), 4.42–3.99 (m, 7H, HC(NHCO2(Glu), HC(NHCO2(Lys), HC(NHCO2(Lys), H2C-Py)), 3.42–3.31 (m, 7H, CHCH2, NCH2(PCTA)), 3.21–3.02 (m, 12H, (CH2)2(PCTA), H2C-Bz, H2CNH(Lys-linker), H2CNH(Lys)), 2.41–2.08 (m, 6H, H2CCO2(Glu), H2CCO2(linker), H2CCO2(linker)), 1.89–1.55 (m, 6H, H2CCH(Glu), H2CCH(Lys-linker), H2CCH(Lys)), 1.55–1.21 (m, 16H, (CH2)2 (Lys), (CH2)2(Lys-Linker), (CH2)4(linker)). ESMS m/z: 1132 [M + H]+. HRESI+ MS: calcd for C51H75N10O17S, 1131.5032 [M + H]+; found, 1131.5011.

9,16,24-Trioxo-1-thioxo-1-((4-((4,7,10-tris(carboxymethyl)-1-oxa-4,7,10-triazacyclododecan-2-yl)methyl)phenyl)amino)-2,8,17,23,25-pentaazaoctacosane-7,22,26,28-tetracarboxylic Acid, Compound 5

The compound was purified by HPLC (method 1; Rt 13.40 min). Yield ∼10 mg (0.076 μmol, ∼23%) after HPLC purification and lyophilization. 1H NMR (DMSO-d6) δ: 8.12 (m, 1H, HNCO(Lys-linker)), 7.80–7.75 (m, 1H, HNCO(Lys)), 7.14 (d, 2H, Bz), 6.79 (d, 2H, Bz), 6.32 (m, 2H, NH(CO)NH), 4.42–3.99 (m, 3H, HC(NHCO2(Glu), HC(NHCO2(Lys), HC(NHCO2(Lys)), 3.49–3.31 (m, 11H, NCH2(DO3A), CHCH2(DO3A), OCH2)), 3.21–3.02 (m, 16H, (CH2)2(DO3A), H2C-Bz, H2CNH(Lys-linker), H2CNH(Lys)), 2.41–2.08 (m, 6H, H2CCO2(Glu), H2CCO2(linker), H2CCO2(linker)), 1.91–1.50 (m, 6H, H2CCH(Glu), H2CCH(Lys-linker), H2CCH(Lys)), 1.50–1.22 (m, 16H, (CH2)2(Lys), (CH2)2(Lys-Linker), (CH2)4(linker). ESMS m/z: 1098 [M + 1]+, HRESI+ MS: calcd for C48H76N9O18S, 1098.5029 [M + H]+; found, 1098.5048.

(14S,29S,33S)-4,7-Dibenzyl-1-(11-(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecan-4-yl)-2,5,8,16,23,31-hexaoxo-3,6,9,15,24,30,32-heptaazapentatriacontane-14,29,33,35-tetracarboxylic Acid, Compound 6

Fmoc-Lys(Boc)-Wang resin (100 mg, 0.43 mM) was allowed to swell with CH2Cl2 (3 mL) followed by DMF (3 mL). A solution of 20% piperidine in DMF (3 × 3 mL) was added to the resin that was then shaken gently on a mechanical shaker for 30 min at ambient temperature. The resin was washed with DMF (3 × 3 mL) and CH2Cl2 (3 × 3 mL). Formation of free amine was assessed by the Kaiser test. After swelling the resin in DMF, a solution of Fmoc-Phe-OH (3 equiv), HBTU (3 equiv), HOBt (3 equiv), and DIPEA (4.0 equiv) in DMF was added and gently shaken for 2 h. The resin was then washed with DMF (3 × 3 mL) and CH2Cl2 (3 × 3 mL). The coupling efficiency was assessed by the Kaiser test. The aforementioned sequence was repeated for two more coupling steps with Fmoc-Phe-OH and CB-TE2A, respectively. The final compound was cleaved from the resin using TFA:CH2Cl2 (1:1) and concentrated under vacuum to produce 8. The concentrated product was purified by using a C18 SepPak Vac 2g column. The product was eluted with a solution 70/30 water/acetonitrile (0.1% TFA in each). ESI-MS: 635 [M]+. To a solution of 8 (20 mg, 31 μmol in 500 μL of DMSO) (27 mg, 47 μmol) and DIEA (50 μL) was added 1, and the reaction mixture was left at ambient temperature for 2 h. The solution was diluted in 10 mL of water and was purified by HPLC (method 1, time (Rt), 20 min). Yield ∼10 mg (0.076 μmol, ∼22%) after HPLC purification and lyophilization. 1H NMR (DMSO-d6): 9.02–8.07 (m, 12H, HNCO(Lys-linker), HNCO(Lys), PhCH2), 6.34 (m, 2H, NH(CO)NH), 4.62 (m, 2H, NHCO2(Phe)), 4.37–4.28 (m, 3H, (m, 3H, HC(NHCO2(Glu), HC(NHCO2(Lys), HC(NHCO2(Lys)), 3.65–3.01 (m, 14H, CH2 N(CB-TE2A), H2CPhe, H2CNH(Lys), H2CNH(Lys)), 2.74–2.41 (m, 20H, NCH2CH2(CB-TE2A), 2.41–2.08 (m, 6H, H2CCO2(Glu), H2CCO2(linker), H2CCO2(linker)), 1.91–1.50 (m, 10H, CH2(CB-TE2A), H2CCH(Glu), H2CCH(Lys-linker), H2CCH(Lys)), 1.56–1.22 (m, 16H, (CH2)2(Lys), (CH2)2(Lys-Linker), (CH2)4(linker). ESMS m/z: 1222 [M + H]+. HRESI+ MS: calcd for C60H91N11O16, 1221.6645; found, 1221.4951.

Copper Complexes of Ligand 3, 4, 5, 6, and 7

Copper compounds [63/65 Cu]3–5 and[63/65 Cu]7 were prepared by the same general procedure as presented for compound 3 below. [63/65Cu]6A–B were prepared by same conditions as described for their radiosynthesis.
[63/65Cu]3. To a solution of Cu(NO3)2 (1 mg, 20 μmol in 100 μL) in deionized water was added 3 (1 mg, 0.95 μmol) in 500 μL of 0.2 M NaOAc. The resulting solution was heated in boiling water for 0.5 h. The solution was purified by HPLC method 2. The retention time for the product was 34 min. Yield: ∼50%. ESIMS m/z: 1115 [M + H]+. HRMS: calcd for C46H70CuN9O17S, 1115.3906 [M + H]+; found, 1115.3828.
[63/65Cu]4. The compound was purified by HPLC method 3. Retention time for the product was at 22 min. Yield: ∼50%. ESIMS m/z: 1192 [M + H]+. HRMS: calcd for C51H73CuN10O17S, 1192.4172 [M + H]+; found, 1192.4364.
[63/65Cu]5. The compound was purified by HPLC method 4. Retention time for the product was at 14 min. Yield: ∼60%. ESIMS m/z: 1160 [M + H]+. HRMS: calcd for C48H76CuN9O18S, 1160.4247 [M + H]+; found, 1160.3828.
[63/65Cu]6A–B .The compound was purified by HPLC method 5. Retention time for the products were at 24 and 26 min. Yield: ∼50%. ESIMS m/z: 1285 [M + H]+. HRMS: calcd for C60H91CuN11O16, 1284.5930 [M + H]+; found, 1284.5786.
[63/65Cu]7. The compound was purified by HPLC method 6. Rt for the product was at 13 min. Yield: ∼55%. ESIMS m/z: 1349 [M + H]+. HRMS: calcd for C60H90CuN11O20, 1348.5650 [M + H]+; found, 1348.5671

64Cu Radiolabeling

Radioligands [64Cu]3–5 and 7 were prepared by the same general method as described for [64Cu]3. For each radiolabeling reaction, approximately 30–40 μg of ligand and in 200 mM NaOAc (purged under N2 for 2–3 min) was incubated with 3–4 mCi 64CuCl2 at pH 5.5–6 for 0.3 h in a water bath at 65 °C. Radiolabeling was monitored by injecting aliquots of 20–40 μL of the solution onto the HPLC. When the reaction reached completion, the reaction mixture was diluted with 1 mL of water then loaded onto a preparative HPLC for purification using method 2, Rt 41 min, for the desired product and Rt 38 min for the free ligand. The radiolabeled product [64Cu]3 was obtained in ∼60–70% radiochemical yield, and the radiochemical purity was >98% as measured by ITLC (Gelman ITLC strips, 10 mM EDTA). HPLC method 2 was used to purify the radiolabeled product [64Cu]3. Rt 34 min for the desired product and Rt 42 min for the free ligand. The specific activity of the probe was 2.9–9.1 GBq/μmol (n = 4). The acidic eluate was neutralized with 50 μL of 1 M Na2(CO3), and the volume of the eluate was reduced under vacuum to dryness. The solid residue was diluted with saline to the desired radioactivity concentration for biodistribution and imaging studies. HPLC method 3 was used for [64Cu]4, Rt = 20–26 min for [64Cu]4 and Rt = 15 min for the free ligand 4. [64Cu]4 was isolated in two peaks, Rt 20–22 min for the first fraction and 23–26 min for the second fraction. On the basis of the initial results (in PET imaging both fractions displayed similar in vivo distributions), only the second fraction was used for all studies. HPLC method 4 was used for [64Cu]5. Retention times for [64Cu]5 and free ligand were and 14.5 and 9.5 min, respectively. The radiotracer [64Cu]7 was purified by HPLC method 6. Rt for [64Cu]7 was at 13 min.
For [64Cu]6A–B, radiolabeling was done in a boiling water bath for 1 h by incubation of 64CuCl2 with the corresponding ligand using 0.2 NaOAc buffer at pH = 7.5–8. HPLC method 5, Rt = 24.9 min (A) and 26.8 min (B) for the desired products and Rt = 19.8 min (A) and 21.5 min (B) for the free ligands. The specific activity of the probe was 2.9 GBq–12.84 GBq/μmol.

NAALADase Assay

The PSMA inhibitory activities of 3–7 and the corresponding copper-labeled analogues were determined using a fluorescence-based assay according to a previously reported procedure. 28 Briefly, lysates of LNCaP cell extracts (25 μL) were incubated with the inhibitor (12.5 μL) in the presence of 4 μM N-acetylaspartylglutamate (NAAG) (12.5 μL) for 120 min. The amount of the glutamate released by NAAG hydrolysis was measured by incubating with a working solution (50 μL) of the Amplex Red glutamic acid kit (Life Technologies, Grand Island, NY) for 60 min. Fluorescence was measured with a VICTOR3 V multilabel plate reader (Perkin-Elmer Inc., Waltham, MA) with excitation at 490 nm and emission at 642 nm. Inhibition curves were determined using semilog plots, and IC50 values were determined at the concentration at which enzyme activity was inhibited by 50%. Enzyme inhibitory constants (Ki values) were generated using the Cheng–Prusoff conversion. (69) Assays were performed in triplicate. Data analysis was performed using GraphPad Prism version 4.00 for Windows (GraphPad Software, San Diego, California).

Cell Lines

Sublines of the androgen-independent PC3 human prostate cancer cell line, originally derived from an advanced androgen independent bone metastasis, were used. These sublines have been modified to express high (PC3 PIP) or possess low (PC3 flu) levels of PSMA and were generously provided by Dr. Warren Heston (Cleveland Clinic). PSMA-expressing (PC3 PIP), nonexpressing (PC3 flu) PCa cell lines, were grown in RPMI 1640 medium (Corning Cellgro, Manassas, VA) containing 10% fetal bovine serum (FBS) (Sigma-Aldrich, St.Louis, MO) and 1% penicillin–streptomycin (Corning Cellgro, Manassas, VA) and PC-3 PIP cells were grown under 20 μg/mL of puromycin to maintain PSMA expression. All cell cultures were maintained in an atmosphere containing 5% carbon dioxide (CO2) at 37.0 °C in a humidified incubator.

Tumor Models

Animal studies were carried out in full compliance with the regulations of the Johns Hopkins Animal Care and Use Committee. Six-to-eight-week-old male, nonobese diabetic (NOD)/severe-combined immunodeficient (SCID) mice (Johns Hopkins Immune Compromised Core) were implanted subcutaneously (sc) with PC3 PIP (PSMA+) and PC3 flu (PSMA−) cells (1 × 106 in 100 μL of HBSS (Corning Cellgro, Manassas, VA) at the forward right and left flanks, respectively. Mice were imaged or used in ex vivo biodistribution assays when the xenografts reached 5– 7 mm in diameter.

Small-Animal PET Imaging and Analysis

Dynamic and whole-body PET and CT images were acquired on an eXplore VISTA small-animal PET (GE Healthcare) and an X-SPECT small SPECT/CT system (Gamma Medica Ideas), respectively. For imaging studies, mice were anesthetized with 3% and maintained under 1.5% isoflurane (v/v). PET-CT Imaging studies were performed on NOD/SCID mice bearing PSMA+ PC3 PIP and PSMA– PC3 flu tumors. Immediately after intravenous injection of [64Cu]3–7, changes in radiotracer accumulation were recorded over the whole body using an imaging sequence consisting of eight frames for a total of 30 min with variable dwell times as described previously. (43, 64) After dynamic imaging, whole-body PET images (two bed positions, 15 min emission per bed position) were acquired at the indicated time points after injection of radiotracer. For binding specificity studies, a mouse was subcutaneously administered with a blocking dose of the known PSMA inhibitor ZJ43 (50 mg/kg) at 30 min before the injection of [64Cu]6B, and another mouse was injected with [64Cu]6B alone. After each PET scan, a CT scan was acquired as 512 projections using a 50 keV beam for anatomic coregistration. PET emission data were corrected for decay and dead time and were reconstructed using the three-dimensional ordered-subsets expectation maximization algorithm. Data were displayed and analyzed using AMIDE software (http://sourceforge.net/amide), and volume-rendered images were generated using Amira 5.2.0 software (Visage Imaging Inc.; http://www.vsg3d.com/amira).

Ex Vivo Biodistribution

Mice bearing PSMA+ PC3 PIP and PSMA– PC3 flu xenografts were injected via the tail vein with 740 kBq (20 μCi) of 64Cu in 200 μL of saline. At 30, 60, 240, and 240 or 300 min postinjection, the mouse was sacrificed by cervical dislocation and the blood immediately collected by cardiac puncture. The heart, lungs, liver, stomach, pancreas, spleen, fat, kidney, muscle, small and large intestines, urinary bladder, PSMA+ PC3 PIP and PSMA– PC3 flu tumors were collected. Each organ was weighed, and the tissue radioactivity was measured with an automated gamma counter (1282 Compugamma CS, Pharmacia/LKBNuclear, Inc., Mt. Waverly, Victoria, Australia). The % ID/g was calculated by comparison with samples of a standard dilution of the initial dose. All measurements were corrected for decay.

Data Analysis

Data are expressed as mean ± standard deviation (SD). Prism software (GraphPAD, San Diego, California) was used to determine statistical significance. Statistical significance was calculated using a paired t test. A P-value <0.0001 was considered significant.

Supporting Information

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Detailed spectral data and supporting PET-CT blocking study image. This material is available free of charge via the Internet at http://pubs.acs.org.

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Author Information

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  • Corresponding Authors
    • Sangeeta Ray Banerjee - Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, Maryland 21287, United States;  Email: [email protected]
    • Martin G. Pomper - Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, Maryland 21287, United States;  Email: [email protected]
  • Authors
    • Mrudula Pullambhatla - Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, Maryland 21287, United States
    • Catherine A. Foss - Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, Maryland 21287, United States
    • Sridhar Nimmagadda - Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, Maryland 21287, United States
    • Riccardo Ferdani - Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15219, United States
    • Carolyn J. Anderson - Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15219, United States
    • Ronnie C. Mease - Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, 1550 Orleans Street, Baltimore, Maryland 21287, United States
  • Notes
    The authors declare no competing financial interest.

Acknowledgment

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We thank the University of Wisconsin Cyclotron Research Group for providing [64Cu]CuCl2. We also thank Nordion and Macrocyclics, Inc., for providing PCTA-Bn-SCN and Oxo-DO3A-Bn-SCN chelating agent, Drs. Cara Ferreira and Russell Redshaw for helpful discussion, and James Fox, Gilbert Green, and Dr. Yuchuan Wang for assistance with imaging and image analysis. We are grateful for the following sources of support: K25 CA148901, NIH NCI U54CA151838, NCI CA134675, and NCI R01 CA093375.

Abbreviations Used

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PSMA

prostate-specific membrane antigen

GCPII

glutamate carboxypeptidase II

NAALADase

N-acetylated-α-linked acidic dipeptidase

PET

positron emission tomography

SPECT

single photon emission computed tomography

NOTA

1,4,7-triazacyclononane-1,4,7-triacetic acid

CB-TE2A

4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane

PCTA

3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene)-3,6,9-triacetic acid

oxo-DO3A

oxa-4,7,1-tetraazacyclododecane-4,7,10-triacetic acid

DOTA

1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid

References

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This article references 69 other publications.

  1. 1
    Ghosh, A.; Heston, W. D. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer J. Cell Biochem. 2004, 91, 528– 539
    Google Scholar
    1
    Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer
    Ghosh, Arundhati; Heston, Warren D. W.
    Journal of Cellular Biochemistry (2004), 91 (3), 528-539CODEN: JCEBD5; ISSN:0730-2312. (Wiley-Liss, Inc.)
    A review. Prostate specific membrane antigen (PSMA), is a unique membrane bound glycoprotein, which is overexpressed manifold on prostate cancer as well as neovasculature of most of the solid tumors, but not in the vasculature of the normal tissues. This unique expression of PSMA makes it an important marker as well as a large extracellular target of imaging agents. PSMA can serve as target for delivery of therapeutic agents such as cytotoxins or radionuclides. PSMA has two unique enzymic functions, folate hydrolase and NAALADase and found to be recycled like other membrane bound receptors through clathrin coated pits. The internalization property of PSMA leads one to consider the potential existence of a natural ligand for PSMA. In this review we have discussed the regulation of PSMA expression within the cells, and significance of its expression in prostate cancer and metastasis.
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  2. 2
    Rajasekaran, A. K.; Anilkumar, G.; Christiansen, J. J. Is prostate-specific membrane antigen a multifunctional protein? Am. J. Physiol., Cell Physiol. 2005, 288, C975– C981
    Google Scholar
    There is no corresponding record for this reference.
  3. 3
    Chang, S. S.; Reuter, V. E.; Heston, W. D.; Gaudin, P. B. Comparison of anti-prostate-specific membrane antigen antibodies and other immunomarkers in metastatic prostate carcinoma Urology 2001, 57, 1179– 1183
    Google Scholar
    3
    Comparison of anti-prostate-specific membrane antigen antibodies and other immunomarkers in metastatic prostate carcinoma
    Chang S S; Reuter V E; Heston W D; Gaudin P B
    Urology (2001), 57 (6), 1179-83 ISSN:.
    OBJECTIVES: To compare the immunohistochemical properties of the 7E11 anti-prostate-specific membrane antigen (anti-PSMA) monoclonal antibody (mAb) with the recently developed anti-PSMA mAb, PM2J004.5, and with other common immunomarkers in metastatic prostate cancer. PSMA is a type II integral membrane glycoprotein highly expressed in prostate cancer cells. The mAb 7E11 is currently used in the radioisotopic evaluation of prostate cancer, and its immunohistochemical properties have been examined in primary prostate cancer specimens. METHODS: We examined 23 formalin-fixed, paraffin-embedded, metastatic prostate carcinoma specimens from various anatomic sites, including bone, lymph node, liver, lung, and soft tissue. Using the biotin-streptavidin method, we performed immunohistochemical reactions with the anti-PSMA mAbs 7E11 and PM2J004.5 and with antibodies to prostate-specific antigen and prostatic acid phosphatase. The immunoreactions were scored by pathologists unaware of the clinical and pathologic data according to a staining intensity scale and the percentage of cells stained. RESULTS: All four mAbs consistently stained the metastatic prostate cancer specimens. In 2 (8.7%) of 23 cases, however, the prostate-specific antigen immunoreaction was negative but the anti-PSMA mAbs had positive staining. Although 7E11 and PM2J004.5 had a similar staining intensity and percentage of cells stained for most specimens, in 3 (13%) of 23 specimens, 7E11 had less intense staining. None of the specimens were negative for all four antibodies. CONCLUSIONS: Anti-PSMA mAbs consistently immunoreacted with metastatic prostate cancer specimens and were positive in instances when prostate-specific antigen staining was negative. The anti-PSMA mAbs demonstrated similar staining patterns; however, in select cases, the PM2J004.5 mAb did show more intense staining. The anti-PSMA mAbs 7E11 and PM2J004.5 are useful in the pathologic evaluation of paraffin-embedded metastatic prostate cancer specimens.
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  4. 4
    Wright, G. L., Jr.; Grob, B. M.; Haley, C.; Grossman, K.; Newhall, K.; Petrylak, D.; Troyer, J.; Konchuba, A.; Schellhammer, P. F.; Moriarty, R. Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy Urology 1996, 48, 326– 334
    Google Scholar
    4
    Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy
    Wright G L Jr; Grob B M; Haley C; Grossman K; Newhall K; Petrylak D; Troyer J; Konchuba A; Schellhammer P F; Moriarty R
    Urology (1996), 48 (2), 326-34 ISSN:0090-4295.
    OBJECTIVES: To determine the expression of prostate-specific membrane antigen (PSMA) before and after androgen-deprivation therapy and to compare PSMA expression with prostate-specific antigen (PSA) expression. METHODS: We studied specimens from 20 patients with prostate cancer undergoing medical or surgical castration or combination androgen-deprivation therapy in whom matched pretreatment and post-treatment tissue specimens were available and 16 patients in whom only a post-treatment specimen was available. The expression of PSMA and PSA in the tissue specimens was determined by immunoperoxidase staining. The extent of staining was calculated by multiplying the percent of antigen-positive tumor cells by the staining intensity to arrive at a stain index for each biomarker. An in vitro study assessed the concentration of PSMA and PSA in extracts of LNCaP cells cultured in the presence or absence of androgen as determined by immunoassays and Western blot analysis. RESULTS: PSMA reactivity was found to be increased in 55% (11 of 20) of post-treatment primary tissues and 100% (4 of 4) of post-treatment metastatic specimens. In contrast, PSA expression was found to be decreased in 70% (14 of 20) of post-treatment primary and 100% (4 of 4) of post-treatment metastatic specimens. Neither type of androgen-deprivation treatment nor tissue sensitivity to androgen deprivation appeared to influence degree of biomarker expression. PSMA was found to be downregulated and PSA upregulated when LNCaP cells were cultured in the presence of testosterone or dihydrotestosterone. CONCLUSIONS: The enhanced expression of PSMA in tissues and LNCaP cells after androgen deprivation suggests that PSMA is upregulated in the majority of prostate carcinomas after androgen treatment. The high expression in metastatic tissues strongly suggests that PSMA may be a clinically useful target for antibody-and genetic-directed therapy of prostate cancer that recurs after androgen deprivation. The mechanism whereby androgens suppress the expression of PSMA, and the association of PSMA with the development of hormone-independent prostate cancers, will require further study.
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  5. 5
    Evans, M. J.; Smith-Jones, P. M.; Wongvipat, J.; Navarro, V.; Kim, S.; Bander, N. H.; Larson, S. M.; Sawyers, C. L. Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 9578– 9582
    Google Scholar
    There is no corresponding record for this reference.
  6. 6
    Perner, S.; Hofer, M. D.; Kim, R.; Shah, R. B.; Li, H.; Moller, P.; Hautmann, R. E.; Gschwend, J. E.; Kuefer, R.; Rubin, M. A. Prostate-specific membrane antigen expression as a predictor of prostate cancer progression Human Pathol. 2007, 38, 696– 701
    Google Scholar
    6
    Prostate-specific membrane antigen expression as a predictor of prostate cancer progression
    Perner, Sven; Hofer, Matthias D.; Kim, Robert; Shah, Rajal B.; Li, Haojie; Moeller, Peter; Hautmann, Richard E.; Gschwend, Juergen E.; Kuefer, Rainer; Rubin, Mark A.
    Human Pathology (2007), 38 (5), 696-701CODEN: HPCQA4; ISSN:0046-8177. (Elsevier Inc.)
    Distinguishing aggressive prostate cancer from indolent disease represents an important clin. challenge, because current therapy may lead to overtreatment of men with limited disease. The prostate-specific membrane antigen (PSMA) is a membrane-bound glycoprotein that is highly restricted to the prostate. Previously, studies analyzing the expression of PSMA have found an up-regulation in correlation with prostate cancer, particularly in advanced cancer. This assocn. is ideal for an application as a prognostic marker. In the current study, we characterized PSMA expression in a high-risk cohort and evaluated its potential use as predictive marker of prostate-specific antigen (PSA) recurrence. PSMA expression was analyzed by immunohistochem. using tissue microarrays composed of tumor samples from 450 patients. Protein intensity was recorded using a semiautomated quant. microscope system (ACIS II; Clarient Chromavision Medical Systems, San Juan Capistrano, CA). PSMA expression levels differed significantly (P < .001) between benign prostatic tissue, localized prostate cancer, and lymph node metastases. Dividing the cohort into high- and low-PSMA expressing cancers based on the median area of pos. staining, we found that high PSMA levels were assocd. with significant increase of PSA recurrence (P = .004). This was independent of clin. parameters such as lymph node tumor burden (lymph node d., >20%; P < .001), extraprostatic extension (P = .017), seminal vesicle invasion (P < .001), and high Gleason score (8-10, P = .006). In a multivariate model, PSMA expression and metastases to pelvic lymph nodes were significantly assocd. with time to PSA recurrence (HR, 1.4; 95% confidence interval, 1.1-2.8, P = .017; and hazard ratio, 5; 95% confidence interval, 2.6-9.7, P < .001, resp.). In summary, PSMA is independently assocd. with PSA recurrence in a high-risk cohort and thus might provide insight into the addnl. use of adjuvant therapy. Validation on other cohorts is required.
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  7. 7
    Sanna, V.; Pintus, G.; Roggio, A. M.; Punzoni, S.; Posadino, A. M.; Arca, A.; Marceddu, S.; Bandiera, P.; Uzzau, S.; Sechi, M. Targeted biocompatible nanoparticles for the delivery of (−)-epigallocatechin 3-gallate to prostate cancer cells J. Med. Chem. 2011, 54, 1321– 1332
    Google Scholar
    7
    Targeted Biocompatible Nanoparticles for the Delivery of (-)-Epigallocatechin 3-Gallate to Prostate Cancer Cells
    Sanna, Vanna; Pintus, Gianfranco; Roggio, Anna Maria; Punzoni, Stefania; Posadino, Anna Maria; Arca, Alessandro; Marceddu, Salvatore; Bandiera, Pasquale; Uzzau, Sergio; Sechi, Mario
    Journal of Medicinal Chemistry (2011), 54 (5), 1321-1332CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Mol. targeted cancer therapy mediated by nanoparticles (NPs) is a promising strategy to overcome the lack of specificity of conventional chemotherapeutic agents. In this context, the prostate-specific membrane antigen (PSMA) has demonstrated a powerful potential for the management of prostate cancer (PCa). Cancer chemoprevention by phytochems. is emerging as a suitable approach for the treatment of early carcinogenic processes. Since (-)-epigallocatechin 3-gallate (EGCG) has shown potent chemopreventive efficacy for PCa, we designed and developed novel targeted NPs in order to selectively deliver EGCG to cancer cells. Herein, to explore the recent concept of "nanochemoprevention", we present a study on EGCG-loaded NPs consisting of biocompatible polymers, functionalized with small mols. targeting PSMA, that exhibited a selective in vitro efficacy against PSMA-expressing PCa cells. This approach could be beneficial for high risk patients and would fulfill a significant therapeutic need, thus opening new perspectives for novel and effective treatment for PCa.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhslyiu7k%253D&md5=8a103de00d04093c1d00f9a8b24732fa
  8. 8
    DiPippo, V. A.; Magargal, W. W.; Moorji, S. M.; Murga, J. D.; Olson, W. C. Antiandrogen modulation of prostate-specific membrane antigen (PSMA): dynamics and synergy with PSMA-targeted therapy ASCO Meet. Abstr. 2013, 31, e16007
    Google Scholar
    There is no corresponding record for this reference.
  9. 9
    Petrylak, D. P.; Kantoff, P. W.; Mega, A. E.; Vogelzang, N. J.; Stephenson, J.; Fleming, M. T.; Stambler, N.; Petrini, M.; Blattman, S.; Israel, R. J. Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): a phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane ASCO Meet. Abstr. 2013, 31, 5018
    Google Scholar
    There is no corresponding record for this reference.
  10. 10
    Rotshteyn, Y.; Mercier, F.; Bruno, R.; Stambler, N.; Israel, R. J.; Wong, V. Correlation of PSMA ADC exposure with reduction in tumor growth rate determined using serial PSA measurements from a phase I clinical trial ASCO Meet. Abstr. 2013, 31, e16047
    Google Scholar
    There is no corresponding record for this reference.
  11. 11
    Hrkach, J.; Von Hoff, D.; Mukkaram Ali, M.; Andrianova, E.; Auer, J.; Campbell, T.; De Witt, D.; Figa, M.; Figueiredo, M.; Horhota, A.; Low, S.; McDonnell, K.; Peeke, E.; Retnarajan, B.; Sabnis, A.; Schnipper, E.; Song, J. J.; Song, Y. H.; Summa, J.; Tompsett, D.; Troiano, G.; Van Geen Hoven, T.; Wright, J.; LoRusso, P.; Kantoff, P. W.; Bander, N. H.; Sweeney, C.; Farokhzad, O. C.; Langer, R.; Zale, S. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile Sci. Transl. Med. 2012, 4, 128ra39
    Google Scholar
    There is no corresponding record for this reference.
  12. 12
    Hillier, S. M.; Maresca, K. P.; Femia, F. J.; Marquis, J. C.; Foss, C. A.; Nguyen, N.; Zimmerman, C. N.; Barrett, J. A.; Eckelman, W. C.; Pomper, M. G.; Joyal, J. L.; Babich, J. W. Preclinical evaluation of novel glutamate–urea–lysine analogues that target prostate-specific membrane antigen as molecular imaging pharmaceuticals for prostate cancer Cancer Res. 2009, 69, 6932– 6940
    Google Scholar
    12
    Preclinical Evaluation of Novel Glutamate-Urea-Lysine Analogues That Target Prostate-Specific Membrane Antigen as Molecular Imaging Pharmaceuticals for Prostate Cancer
    Hillier, Shawn M.; Maresca, Kevin P.; Femia, Frank J.; Marquis, John C.; Foss, Catherine A.; Nguyen, Nghi; Zimmerman, Craig N.; Barrett, John A.; Eckelman, William C.; Pomper, Martin G.; Joyal, John L.; Babich, John W.
    Cancer Research (2009), 69 (17), 6932-6940CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
    Prostate-specific membrane antigen (PSMA) is expressed in normal human prostate epithelium and is highly up-regulated in prostate cancer. We previously reported a series of novel small mol. inhibitors targeting PSMA. Two compds., MIP-1072, (S)-2-(3-((S)-1-carboxy-5-(4-iodobenzylamino)pentyl)ureido)pentanedioic acid, and MIP-1095, (S)-2-(3-((S)-1-carboxy-5-(3-(4-iodophenyl)ureido)pentyl)ureido)pentanedioic acid, were selected for further evaluation. MIP-1072 and MIP-1095 potently inhibited the glutamate carboxypeptidase activity of PSMA (Ki = 4.6 ± 1.6 nM and 0.24 ± 0.14 nM, resp.) and, when radiolabeled with 123I, exhibited high affinity for PSMA on human prostate cancer LNCaP cells (Kd = 3.8 ± 1.3 nM and 0.81 ± 0.39 nM, resp.). The assocn. of [123I]MIP-1072 and [123I]MIP-1095 with PSMA was specific; there was no binding to human prostate cancer PC3 cells, which lack PSMA, and binding was abolished by coincubation with a structurally unrelated NAALADase inhibitor, 2-(phosphonomethyl)pentanedioic acid (PMPA). [123I]MIP-1072 and [123I]MIP-1095 internalized into LNCaP cells at 37°C. Tissue distribution studies in mice showed 17.3 ± 6.3% (at 1 h) and 34.3 ± 12.7% (at 4 h) injected dose per g of LNCaP xenograft tissue, for [123I]MIP-1072 and [123I]MIP-1095, resp. [123I]MIP-1095 exhibited greater tumor uptake but slower washout from blood and nontarget tissues compared with [123I]MIP-1072. Specific binding to PSMA in vivo was shown by competition with PMPA in LNCaP xenografts, and the absence of uptake in PC3 xenografts. The uptake of [123I]MIP-1072 and [123I]MIP-1095 in tumor-bearing mice was corroborated by single-photon emission computed tomog./computed tomog. (SPECT/CT) imaging. PSMA-specific radiopharmaceuticals should provide a novel mol. targeting option for the detection and staging of prostate cancer.
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  13. 13
    Mease, R. C.; Foss, C. A.; Pomper, M. G. PET imaging in prostate cancer: focus on prostate-specific membrane antigen Curr. Top. Med. Chem. 2013, 13, 951– 962
    Google Scholar
    13
    PET imaging in prostate cancer: focus on prostate-specific membrane antigen
    Mease, Ronnie C.; Foss, Catherine A.; Pomper, Martin G.
    Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2013), 13 (8), 951-962CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
    A review. Prostate cancer (PCa) is the second leading cause of cancer-related death in American men. Positron emission tomog./computed tomog. (PET/CT) with emerging radiopharmaceuticals promises accurate staging of primary disease, restaging of recurrent disease, detection of metastatic lesions and, ultimately, for predicting the aggressiveness of disease. Prostate-specific membrane antigen (PSMA) is a well-characterized imaging biomarker of PCa. Because PSMA levels are directly related to androgen independence, metastasis and progression, PSMA could prove an important target for the development of new radiopharmaceuticals for PET. Preclin. data for new PSMA-based radiotracers are discussed and include new 89Zr- and 64Cu-labeled anti-PSMA antibodies and antibody fragments, 64Cu-labeled aptamers, and 11C-, 18F-, 68Ga-, 64Cu-, and 86Y-labeled low mol. wt. inhibitors of PSMA. Several of these agents, namely 68Ga- HBED-CC conjugate 15, 18F-DCFBC 8, and BAY1075553 are particularly promising, each having detected sites of PCa in initial clin. studies. These early clin. results suggest that PET/CT using PSMA-targeted agents, esp. with compds. of low mol. wt., will make valuable contributions to the management of PCa.
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  14. 14
    Cho, S. Y.; Gage, K. L.; Mease, R. C.; Senthamizhchelvan, S.; Holt, D. P.; Jeffrey-Kwanisai, A.; Endres, C. J.; Dannals, R. F.; Sgouros, G.; Lodge, M.; Eisenberger, M. A.; Rodriguez, R.; Carducci, M. A.; Rojas, C.; Slusher, B. S.; Kozikowski, A. P.; Pomper, M. G. Biodistribution, tumor detection, and radiation dosimetry of 18F–DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer J. Nucl. Med. 2012, 53, 1883– 1891
    Google Scholar
    There is no corresponding record for this reference.
  15. 15
    Afshar-Oromieh, A.; Malcher, A.; Eder, M.; Eisenhut, M.; Linhart, H. G.; Hadaschik, B. A.; Holland-Letz, T.; Giesel, F. L.; Kratochwil, C.; Haufe, S.; Haberkorn, U.; Zechmann, C. M. PET imaging with a [(68)Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions Eur. J. Nucl. Med. Mol. Imaging 2012, 40, 486– 495
    Google Scholar
    There is no corresponding record for this reference.
  16. 16
    Barrett, J. A.; Coleman, R. E.; Goldsmith, S. J.; Vallabhajosula, S.; Petry, N. A.; Cho, S.; Armor, T.; Stubbs, J. B.; Maresca, K. P.; Stabin, M. G.; Joyal, J. L.; Eckelman, W. C.; Babich, J. W. First-in-man evaluation of 2 high-affinity PSMA-avid small molecules for imaging prostate cancer J. Nucl. Med. 2013, 54, 380– 387
    Google Scholar
    There is no corresponding record for this reference.
  17. 17
    Maresca, K. P.; Hillier, S. M.; Lu, G.; Marquis, J. C.; Zimmerman, C. N.; Eckelman, W. C.; Joyal, J. L.; Babich, J. W. Small molecule inhibitors of PSMA incorporating technetium-99m for imaging prostate cancer: effects of chelate design on pharmacokinetics Inorg. Chim. Acta 2012, 389, 168– 172
    Google Scholar
    17
    Small molecule inhibitors of PSMA incorporating technetium-99m for imaging prostate cancer: Effects of chelate design on pharmacokinetics
    Maresca, Kevin P.; Hillier, Shawn M.; Lu, Genliang; Marquis, John C.; Zimmerman, Craig N.; Eckelman, William C.; Joyal, John L.; Babich, John W.
    Inorganica Chimica Acta (2012), 389 (), 168-175CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)
    Single amino acid chelate (SAAC) systems for the complexation of the M(CO)3 moiety (M = Tc/Re) have been successfully incorporated into novel synthetic strategies for radiopharmaceuticals and evaluated in a variety of biol. applications. However, the lipophilicity of the first generation of 99mTc(CO)3 complexes has resulted in substantial hepatobiliary uptake when examd. either as lysine derivs. or integrated into biol. active small mols. and peptides. Here, we designed, synthesized, and evaluated novel polar functionalized imidazole derived SAAC systems (SAAC II) which have been chem. modified to promote overall 99mTc(CO)3L3 complex hydrophilicity with the intent of reducing non-target effects and enhancing renal clearance of prostate specific membrane antigen (PSMA) targeting small mols. The 99mTc-labeled compds. were prepd., purified, and evaluated for stability, lipophilicity, and tissue distribution in LNCaP xenograft mice. The Glu-urea-Lys-C11 analogs were prepd. with a variety of chelators to form (19R,23S)-1-(X)-2-((Y)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-19,23,25-tricarboxylic acid where X = Y = (methyl)pyridin-2-yl (6), X = Y = (methyl)-1H-imidazol-2-yl (7), X = (methyl)pyridin-2-yl, Y = carboxymethyl (8), X = Y = 1-(carboxymethyl)-1H-imidazol-2-yl (9), X = 1-(carboxymethyl)-1H-imidazol-2-yl, Y = carboxymethyl (10), and X = Y = 1-(1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl) (11). 99mTc labeling was achieved at ligand concns. as low as 10-6 M and the complexes were stable (>90%) for 24 h. These new SAAC II chelators were evaluated for their influence on binding of the Glu-urea-Lys-C11 analogs to PSMA-pos. LNCaP cells and compared to pyridine- and N-methylimidazole-contg. SAAC ligands. Tissue distribution of the 99mTc-complexes contg. the more polar chelators, 9 and 11, demonstrated decreased liver (<2% ID/g) and increased LNCaP tumor (>11% ID/g) accumulation at 1 h post-injection.
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  18. 18
    Nedrow-Byers, J. R.; Moore, A. L.; Ganguly, T.; Hopkins, M. R.; Fulton, M. D.; Benny, P. D.; Berkman, C. E. PSMA-targeted SPECT agents: Mode of binding effect on in vitro performance Prostate 2013, 73, 355– 362
    Google Scholar
    There is no corresponding record for this reference.
  19. 19
    Lu, G.; Maresca, K. P.; Hillier, S. M.; Zimmerman, C. N.; Eckelman, W. C.; Joyal, J. L.; Babich, J. W. Synthesis and SAR of 99mTc/Re-Labeled Small Molecule Prostate Specific Membrane Antigen Inhibitors with Novel Polar Chelates Biorg. Med. Chem. Lett. 2013, 23, 1557– 1563
    Google Scholar
    19
    Synthesis and SAR of 99mTc/Re-labeled small molecule prostate specific membrane antigen inhibitors with novel polar chelates
    Lu, Genliang; Maresca, Kevin P.; Hillier, Shawn M.; Zimmerman, Craig N.; Eckelman, William C.; Joyal, John L.; Babich, John W.
    Bioorganic & Medicinal Chemistry Letters (2013), 23 (5), 1557-1563CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    Prostate specific membrane antigen (PSMA) is recognized as an attractive mol. target for the development of radiopharmaceuticals to image and potentially treat metastatic prostate cancer. A series of novel 99mTc/Re-tricarbonyl radiolabeled PSMA inhibitors were therefore synthesized by the attachment of glutamate-urea-lysine (Glu-urea-Lys) and glutamate-urea-glutamate (Glu-urea-Glu) pharmacophore to single amino acid chelate (SAAC) where the SAAC ligand was either bis(pyridin-2-ylmethyl)amino (DPA), bis((1-methyl-1H-imidazol-2-yl)methyl)amino (NMI), bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino (CIM) or bis((1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino (TIM). The in vitro binding affinity of the rhenium complexes was evaluated using PSMA-expressing human prostate cancer LNCaP cells. IC50 values ranged from 3.8 ± 2 to >2000 nM. A linker between the SAAC chelate and pharmacophore was required for high affinity binding. However, extending the length of the linker did not substantially improve binding. PSMA binding was also influenced by the nature of the SAAC chelate. One of the most potent compds., 23b (IC50 = 4.8 ± 2.7 nM), was radiolabeled with technetium tricarbonyl ({99mTc(CO)3}+) to afford the {99mTc(CO)3}+ complex in excellent yield and high purity. This effort led to the identification of a diverse series of promising high affinity {99mTc(CO)3}+ radiolabeled PSMA inhibitors.
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    Nedrow-Byers, J. R.; Jabbes, M.; Jewett, C.; Ganguly, T.; He, H.; Liu, T.; Benny, P.; Bryan, J. N.; Berkman, C. E. A phosphoramidate-based prostate-specific membrane antigen-targeted SPECT agent Prostate 2012, 72, 904– 912
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  21. 21
    Banerjee, S. R.; Foss, C. A.; Castanares, M.; Mease, R. C.; Byun, Y.; Fox, J. J.; Hilton, J.; Lupold, S. E.; Kozikowski, A. P.; Pomper, M. G. Synthesis and evaluation of technetium-99m- and rhenium-labeled inhibitors of the prostate-specific membrane antigen (PSMA) J. Med. Chem. 2008, 51, 4504– 4517
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    21
    Synthesis and Evaluation of Technetium-99m- and Rhenium-Labeled Inhibitors of the Prostate-Specific Membrane Antigen (PSMA)
    Banerjee, Sangeeta R.; Foss, Catherine A.; Castanares, Mark; Mease, Ronnie C.; Byun, Youngjoo; Fox, James J.; Hilton, John; Lupold, Shawn E.; Kozikowski, Alan P.; Pomper, Martin G.
    Journal of Medicinal Chemistry (2008), 51 (15), 4504-4517CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for imaging and therapy of cancer. We prepd. seven 99mTc/Re-labeled compds. by attaching known Tc/Re chelating agents to an amino-functionalized PSMA inhibitor (lys-NHCONH-glu) with or without a variable length linker moiety. Ki values ranged from 0.17 to 199 nM. Ex vivo biodistribution and in vivo imaging demonstrated the degree of specific binding to engineered PSMA+ PC3 PIP tumors. PC3-PIP cells are derived from PC3 that have been transduced with the gene for PSMA. Despite demonstrating nearly the lowest PSMA inhibitory potency of this series, [99mTc(CO)3(L1)]+ (L1 = (2-pyridylmethyl)2N(CH2)4CH(CO2H)NHCO-(CH2)6CO-NH-lys-NHCONH-glu) showed the highest, most selective PIP tumor uptake, at 7.9 ± 4.0% injected dose per g of tissue at 30 min postinjection. Radioactivity cleared from nontarget tissues to produce a PIP to flu (PSMA-PC3) ratio of 44:1 at 120 min postinjection. PSMA can accommodate the steric requirements of 99mTc/Re complexes within PSMA inhibitors, the best results achieved with a linker moiety between the .vepsiln. amine of the urea lysine and the chelator.
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  22. 22
    Kularatne, S. A.; Zhou, Z.; Yang, J.; Post, C. B.; Low, P. S. Design, synthesis, and preclinical evaluation of prostate-specific membrane antigen targeted (99m)Tc-radioimaging agents Mol. Pharmaceutics 2009, 6, 790– 800
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    22
    Design, Synthesis, and Preclinical Evaluation of Prostate-Specific Membrane Antigen Targeted 99mTc-Radioimaging Agents
    Kularatne, Sumith A.; Zhou, Zhigang; Yang, Jun; Post, Carol B.; Low, Philip S.
    Molecular Pharmaceutics (2009), 6 (3), 790-800CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    The high mortality and financial burden assocd. with prostate cancer can be partly attributed to a lack of sensitive screening methods for detection and staging of the disease. Guided by in silico docking studies using the crystal structure of PSMA, we designed and synthesized a series of PSMA-targeted 99mTc-chelate complexes for imaging PSMA-expressing human prostate cancer cells (LNCaP cell line). Of the six targeted radioimaging agents synthesized, three were found to bind LNCaP cells with low nanomolar affinity. Moreover, the same three PSMA-targeted imaging agents were shown to localize primarily to LNCaP tumor xenografts in nu/nu mice, with an av. of 9.8 ± 2.4% injected dose/g tissue accumulating in the tumor and only 0.11% injected dose/g tissue retained in the muscle at 4 h postinjection. Collectively, these high affinity, PSMA-specific radioimaging agents demonstrate significant potential for use in localizing prostate cancer masses, monitoring response to therapy, detecting prostate cancer recurrence following surgery, and selecting patients for subsequent PSMA-targeted chemotherapy.
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  23. 23
    Zhang, Y.; DiFilipp, F.; Doke, A.; Huang, J.; Heston, W.; Huang, S. Preliminary micro-SPECT and biodistribution study of a novel Tc99m-labeled PSMA tracer derived from RBI1033 J. Nucl. Med. Meet. Abstr. 2012, 53 (Suppl 1) 1661
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  24. 24
    Schafer, M.; Bauder-Wust, U.; Leotta, K.; Zoller, F.; Mier, W.; Haberkorn, U.; Eisenhut, M.; Eder, M. A dimerized urea-based inhibitor of the prostate-specific membrane antigen for 68Ga-PET imaging of prostate cancer EJNMMI Res. 2012, 2, 23
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    24
    A dimerized urea-based inhibitor of the prostate-specific membrane antigen for 68Ga-PET imaging of prostate cancer
    Schafer Martin; Bauder-Wust Ulrike; Leotta Karin; Zoller Frederic; Mier Walter; Haberkorn Uwe; Eisenhut Michael; Eder Matthias
    EJNMMI research (2012), 2 (1), 23 ISSN:.
    UNLABELLED: BACKGROUND: Alternative positron-emission tomography (PET) probes like labeled inhibitors of the prostate-specific membrane antigen (PSMA) are of emerging clinical impact as they show the ability to image small lesions of recurrent prostate cancer. Here, the dimerization of the pharmacophore Glu-ureido-Lys via the 68Ga chelator N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) was investigated to further improve the binding characteristics and pharmacokinetics. METHODS: The peptidomimetic structures were synthesized by solid-phase chemistry, and the resulting products were coupled with the respective 2,3,5,6-tetrafluorophenol esters of HBED-CC to form the monomeric reference and the dimeric Glu-ureido-Lys derivative. The binding properties were analyzed in competitive binding, internalization, and cell surface retention experiments. PET images and biodistribution data were obtained 1 h after injection in BALB/c nu/nu mice bearing LNCaP tumor xenografts. RESULTS: Cell binding data revealed significant better binding properties of the dimer (IC50 = 3.9 ± 1.8 nM; IC50 (monomer) = 12.1 ± 2.1 nM). The inhibition potency investigated by the enzyme-based NAALADase assay confirmed these results. Specific internalization in LNCaP cells was demonstrated for both, the monomer and dimer. As shown by efflux measurements, the dimeric compound was more effectively retained on the cell surface, resulting in advanced in vivo properties (T/BMonomer = 9.2; T/BDimer = 26.5). CONCLUSIONS: The dimeric [68Ga]7 is a promising imaging agent for PSMA-expressing tumors as it shows higher tumor uptake while observing more favorable background clearance. As compared to the respective monomer, the higher affinity and prolonged tumor retention additionally represent promising features and warrant further evaluation regarding 68Ga-PET imaging of PSMA expression.
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  25. 25
    Eder, M.; Schafer, M.; Bauder-Wust, U.; Hull, W. E.; Wangler, C.; Mier, W.; Haberkorn, U.; Eisenhut, M. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging Bioconjugate Chem. 2012, 23, 688– 697
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    25
    68Ga-Complex Lipophilicity and the Targeting Property of a Urea-Based PSMA Inhibitor for PET Imaging
    Eder, Matthias; Schaefer, Martin; Bauder-Wuest, Ulrike; Hull, William-Edmund; Waengler, Carmen; Mier, Walter; Haberkorn, Uwe; Eisenhut, Michael
    Bioconjugate Chemistry (2012), 23 (4), 688-697CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    Urea-based inhibitors of the prostate-specific membrane antigen (PSMA) represent low-mol.-wt. pepidomimetics showing the ability to image PSMA-expressing prostate tumors. The highly efficient, acyclic Ga(III) chelator N,N'-bis [2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N'- diacetic acid (HBED-CC) was introduced as a lipophilic side chain into the hydrophilic pharmacophore Glu-NH-CO-NH-Lys which was found favorable to interact with the PSMA "active binding site". This report describes the syntheses, in vitro binding analyses, and biodistribution data of the radiogallium labeled PSMA inhibitor Glu-NH-CO-NH-Lys(Ahx)-HBED-CC in comparison to the corresponding DOTA conjugate. The binding properties were analyzed using competitive cell binding and enzyme-based assays followed by internalization expts. Compared to the DOTA-conjugate, the HBED-CC deriv. showed reduced unspecific binding and considerable higher specific internalization in LNCaP cells. The 68Ga complex of the HBED-CC ligand exhibited higher specificity for PSMA expressing tumor cells resulting in improved in vivo properties. 68Ga labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC showed fast blood and organ clearances, low liver accumulation, and high specific uptake in PSMA expressing organs and tumor. It could be demonstrated that the PET-imaging property of a urea-based PSMA inhibitor could significantly be improved with HBED-CC.
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  26. 26
    Banerjee, S. R.; Pullambhatla, M.; Byun, Y.; Nimmagadda, S.; Green, G.; Fox, J. J.; Horti, A.; Mease, R. C.; Pomper, M. G. 68Ga-labeled inhibitors of prostate-specific membrane antigen (PSMA) for imaging prostate cancer J. Med. Chem. 2010, 53, 5333– 5341
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    26
    68Ga-Labeled Inhibitors of Prostate-Specific Membrane Antigen (PSMA) for Imaging Prostate Cancer
    Banerjee, Sangeeta Ray; Pullambhatla, Mrudula; Byun, Youngjoo; Nimmagadda, Sridhar; Green, Gilbert; Fox, James J.; Horti, Andrew; Mease, Ronnie C.; Pomper, Martin G.
    Journal of Medicinal Chemistry (2010), 53 (14), 5333-5341CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Gallium-68 is a generator-produced radionuclide for positron emission tomog. (PET) that is being increasingly used for radiolabeling of tumor-targeting peptides. Compds. [68Ga]3 and [68Ga]6 are high-affinity urea-based inhibitors of the prostate-specific membrane antigen (PSMA) that were synthesized in decay-uncorrected yields ranging from 60% to 70% and radiochem. purities of more than 99%. Compd. [68Ga]3 demonstrated 3.78 ± 0.90% injected dose per g of tissue (%ID/g) within PSMA+ PIP tumor at 30 min postinjection, while [68Ga]6 showed a 2 h PSMA+ PIP tumor uptake value of 3.29 ± 0.77 %ID/g. Target (PSMA+ PIP) to nontarget (PSMA- flu) ratios were 4.6 and 18.3, resp., at those time points. Both compds. delineated tumor clearly by small animal PET. The urea series of imaging agents for PSMA can be radiolabeled with 68Ga, a cyclotron-free isotope useful for clin. PET studies, with maintenance of target specificity.
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  27. 27
    Banerjee, S. R.; Pullambhatla, M.; Shallal, H.; Lisok, A.; Mease, R. C.; Pomper, M. G. A Modular Strategy to Prepare Multivalent Inhibitors of Prostate-Specific Membrane Antigen (PSMA) Oncotarget 2011, 2, 1244– 1253
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    27
    A modular strategy to prepare multivalent inhibitors of prostate-specific membrane antigen (PSMA)
    Banerjee Sangeeta Ray; Pullambhatla Mrudula; Shallal Hassan; Lisok Ala; Mease Ronnie C; Pomper Martin G
    Oncotarget (2011), 2 (12), 1244-53 ISSN:.
    We have developed a modular scaffold for preparing high-affinity, homo-multivalent inhibitors of the prostate-specific membrane antigen (PSMA) for imaging and therapy of prostate cancer (PCa). Our system contains a lysine-based (μ-, e-) dialkyne residue for incorporating a PSMA binding Lys-Glu urea motif exploiting click chemistry and a second lysine residue for subsequent modification with an imaging or therapeutic moiety. The utility of the multivalent scaffold was examined by synthesizing bivalent compounds 2 and 3 and comparing them with the monovalent analog 1. Determination of inhibition constants (Ki) revealed that bivalent 2 (0.2 nM) and 3 (0.08 nM) are significantly more potent (~ 5 fold and ~ 11 fold, respectively) inhibitors of PSMA than monovalent 1 (0.9 nM). A single photon emission computed tomography (SPECT)-CT imaging study of [111In]3 demonstrated high and specific uptake in PSMA+ PC-3 PIP tumor until at least 48 h post-injection, with rapid clearance from non-target tissues, including kidney. A biodistribution study revealed that [111In]3 demonstrated 34.0 ± 7.5 percent injected dose per gram of tissue in PSMA+ tumor at 24 h post-injection and was capable of generating target-to-non-target ratios of ~ 379 in PSMA+ PC-3 PIP tumors vs. isogenic PSMA-negative PC3-flu tumors in vivo. The click chemistry approach affords a convenient strategy toward multivalent PSMA inhibitors of enhanced affinity and superior pharmacokinetics for imaging.
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  28. 28
    Banerjee, S. R.; Pullambhatla, M.; Byun, Y.; Nimmagadda, S.; Foss, C. A.; Green, G.; Fox, J. J.; Lupold, S. E.; Mease, R. C.; Pomper, M. G. Sequential SPECT and optical imaging of experimental models of prostate cancer with a dual modality inhibitor of the prostate-specific membrane antigen Angew. Chem. 2011, 50, 9167– 9170
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  29. 29
    Chen, Z.; Penet, M. F.; Nimmagadda, S.; Li, C.; Banerjee, S. R.; Winnard, P. T., Jr.; Artemov, D.; Glunde, K.; Pomper, M. G.; Bhujwalla, Z. M. PSMA-targeted theranostic nanoplex for prostate cancer therapy ACS Nano 2012, 6, 7752– 7762
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    29
    PSMA-Targeted Theranostic Nanoplex for Prostate Cancer Therapy
    Chen, Zhihang; Penet, Marie-France; Nimmagadda, Sridhar; Li, Cong; Banerjee, Sangeeta R.; Winnard, Paul T.; Artemov, Dmitri; Glunde, Kristine; Pomper, Martin G.; Bhujwalla, Zaver M.
    ACS Nano (2012), 6 (9), 7752-7762CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Theranostic imaging, where diagnosis is combined with therapy, is particularly suitable for a disease that is as complex as cancer, esp. now that genomic and proteomic profiling can provide an extensive "fingerprint" of each tumor. With such information, theranostic agents can be designed to personalize treatment and minimize damage to normal tissue. Here we have developed a nanoplex platform for theranostic imaging of prostate cancer (PCa). In these proof-of-principle studies, a therapeutic nanoplex contg. multimodal imaging reporters was targeted to prostate-specific membrane antigen (PSMA), which is expressed on the cell surface of castrate-resistant PCa. The nanoplex was designed to deliver small interfering RNA (siRNA) along with a prodrug enzyme to PSMA-expressing tumors. Each component of the nanoplex was carefully selected to evaluate its diagnostic aspect of PSMA imaging and its therapeutic aspects of siRNA-mediated down-regulation of a target gene and the conversion of a prodrug to cytotoxic drug, using noninvasive multimodality imaging. Studies performed using two variants of human PC3-PCa cells and tumors, one with high PSMA expression level and another with negligible expression levels, demonstrated PSMA-specific uptake. In addn., down-regulation of the selected siRNA target, choline kinase (Chk), and the conversion of the nontoxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU) were also demonstrated with noninvasive imaging. The nanoplex was well-tolerated and did not induce liver or kidney toxicity or a significant immune response. The nanoplex platform described can be easily modified and applied to different cancers, receptors, and pathways to achieve theranostic imaging, as a single agent or in combination with other treatment modalities.
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  30. 30
    Hao, G.; Kumar, A.; Dobin, T.; Oz, O. K.; Hsieh, J. T.; Sun, X. A multivalent approach of imaging probe design to overcome an endogenous anion binding competition for noninvasive assessment of prostate specific membrane antigen Mol. Pharmacol. 2013, 10, 2975– 2985
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    There is no corresponding record for this reference.
  31. 31
    Banerjee, S. R.; Pullambhatla, M.; Byun, Y.; Nimmagadda, S.; Baidoo, K. E.; Brechbiel, M. W.; Mease, R. C.; Pomper, M. G. Preclinical Evaluation of 86Y-Labeled Inhibitors of Prostate Specific Membrane Antigen. J. Labelled Compd. Radiopharm. 2011, 54, Suppl S1, p S65.
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    There is no corresponding record for this reference.
  32. 32
    Holland, J. P.; Divilov, V.; Bander, N. H.; Smith-Jones, P. M.; Larson, S. M.; Lewis, J. S. 89Zr–DFO–J591 for immunoPET of prostate-specific membrane antigen expression in vivo J. Nucl. Med. 2010, 51, 1293– 1300
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    There is no corresponding record for this reference.
  33. 33
    Viola-Villegas, N.; Evans, H.; Bartlett, D.; Wu, A.; Lewis, J. Preclinical development of Zr-89 labeled anti-PSMA minibody and cys-diabody J Nucl. Med. Meet. Abstr. 2012, 53, 347
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    There is no corresponding record for this reference.
  34. 34
    Ray Banerjee, S.; Pullambhatla, M.; Foss, C. A.; Falk, A.; Byun, Y.; Nimmagadda, S.; Mease, R. C.; Pomper, M. G. Effect of chelators on the pharmacokinetics of (99m)Tc-labeled imaging agents for the prostate-specific membrane antigen (PSMA) J. Med. Chem. 2013, 56, 6108– 6121
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    34
    Effect of Chelators on the Pharmacokinetics of 99mTc-Labeled Imaging Agents for the Prostate-Specific Membrane Antigen (PSMA)
    Ray Banerjee, Sangeeta; Pullambhatla, Mrudula; Foss, Catherine A.; Falk, Alexander; Byun, Youngjoo; Nimmagadda, Sridhar; Mease, Ronnie C.; Pomper, Martin G.
    Journal of Medicinal Chemistry (2013), 56 (15), 6108-6121CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Technetium-99m, the most commonly used radionuclide in nuclear medicine, can be attached to biol. important mols. through a variety of chelating agents, the choice of which depends upon the imaging application. The prostate-specific membrane antigen (PSMA) is increasingly recognized as an important target for imaging and therapy of prostate cancer (PCa). Three different 99mTc-labeling methods were employed to investigate the effect of the chelator on the biodistribution and PCa tumor uptake profiles of 12 new urea-based PSMA-targeted radiotracers. This series includes hydrophilic ligands for radiolabeling with the [99mTc(CO)3]+ core (L8-L10), traditional NxSy-based chelating agents with varying charge and polarity for the 99mTc-oxo core (L11-L18), and a 99mTc-organohydrazine-labeled radioligand (L19). 99mTc(I)-Tricarbonyl-labeled [99mTc]L8 produced the highest PSMA+ PC3 PIP to PSMA- PC3 flu tumor ratios and demonstrated the lowest retention in normal tissues including kidney after 2 h. These results suggest that choice of chelator is an important pharmacokinetic consideration in the development of 99mTc-labeled radiopharmaceuticals targeting PSMA.
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  35. 35
    Wadas, T. J.; Wong, E. H.; Weisman, G. R.; Anderson, C. J. Copper chelation chemistry and its role in copper radiopharmaceuticals Curr. Pharm. Des. 2007, 13, 3– 16
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    Copper chelation chemistry and its role in copper radiopharmaceuticals
    Wadas, T. J.; Wong, E. H.; Weisman, G. R.; Anderson, C. J.
    Current Pharmaceutical Design (2007), 13 (1), 3-16CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
    A review. Mol. imaging is an important scientific discipline that plays a major role in clin. medicine and pharmaceutical development. While several imaging modalities including x-ray computed tomog. and magnetic resonance imaging generate high-resoln. anatomical images, positron emission tomog. (PET) and single photon emission computed tomog. offer insight into the physiol. processes that occur within a living organism. Of these two nuclear medicine imaging techniques, PET has advantages with respect to sensitivity and resoln., and this has led to the prodn. and development of many positron emitting radionuclides that include non-traditional radionuclides of the transition metals. Copper-64 (t1/2 = 12.7 h, β+: 17.4%, Eβ+max = 656 keV; β-: 39%, Eβ-max = 573 keV) has emerged as an important positron emitting radionuclide that has the potential for use in diagnostic imaging and radiotherapy. However, 64Cu must be delivered to the living system as a stable complex that is attached to a biol. targeting mol. for effective imaging and therapy. Therefore, significant research has been devoted to the development of ligands that can stably chelate 64Cu. This review discusses the necessary characteristics of an effective 64Cu chelator, while highlighting the development and evaluation of 64Cu-complexes attached to biol.-targeted ligands.
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  36. 36
    Connett, J. M.; Anderson, C. J.; Guo, L. W.; Schwarz, S. W.; Zinn, K. R.; Rogers, B. E.; Siegel, B. A.; Philpott, G. W.; Welch, M. J. Radioimmunotherapy with a 64Cu-labeled monoclonal antibody: a comparison with 67Cu Proc. Natl. Acad. Sci. U. S. A. 1996, 93, 6814– 6818
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    Radioimmunotherapy with a 64Cu-labeled monoclonal antibody: a comparison with 67Cu
    Connett, Judith M.; Anderson, Carolyn J.; Guo, Li-Wu; Schwarz, Sally W.; Zinn, Kurt R.; Rogers, Buck E.; Siegel, Barry A.; Philpott, Gordon; Welch, Michael J.
    Proceedings of the National Academy of Sciences of the United States of America (1996), 93 (13), 6814-6818CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    67Cu (t1/2 = 62 h) has demonstrated potential as a radionuclide for radioimmunotherapy, but limited availability severely restricts its widespread use. 64Cu (t1/2 = 12.8 h) has been shown to have comparable effectiveness in vitro and in vivo. The present study was undertaken to examine the therapeutic potential of 64Cu- and 67Cu-bromoacetamidobenzyl-1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (BAT)-2-iminothiolane (2IT)-1A3 (1A3 is a mouse anti-human colorectal cancer mAb) for treatment of GW39 human colon carcinoma carried in hamster thighs. Hamsters were injected with 64Cu- or 67C-BAT-2IT-1A3 or Cu-labeled nonspecific IgG (MOPC) or saline. Hamsters were killed 6-7 mo after therapy or when tumors were ≥10 g. Of the hamsters with small tumors (mean wt. 0.43 ± 0.25 g), 87.5% were disease-free 7 mo after treatment with 2 mCi (1 Ci = 37 GBq) of 64Cu-BAT-2IT-1A3 or 0.4 mCi of 67Cu-BAT-2IT-1A3. The mean tumor doses at these activities of 64Cu- and 67Cu-BAT-2IT-1A3 were 586 and 1269 rad (1 rad = 0.01 Gy), resp. In contrast, 76% of hamsters treated with 2 mCi of 64Cu-BAT-2IT-MOPC or 0.4 mCi of 67Cu-BAT-2IT-MOPC had to be killed before 6 mo because of tumor regrowth. When hamsters with larger tumors (mean wt. 0.66 ± 0.11 g) were treated with 64Cu- or 67Cu-BAT-2IT-1A3, survival was extended compared with controls, but only one animal remained tumor-free to 6 mo. These results demonstrate that 64Cu- and 67Cu-BAT-2IT-1A3 given in a single administered dose can eradicate small tumors without significant host toxicity, but addnl. strategies to deliver higher tumor doses will be needed for larger tumors.
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  37. 37
    Blower, P. J.; Lewis, J. S.; Zweit, J. Copper radionuclides and radiopharmaceuticals in nuclear medicine Nucl. Med. Biol. 1996, 23, 957– 980
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    Copper radionuclides and radiopharmaceuticals in nuclear medicine
    Blower, Philip J.; Lewis, Jason S.; Zweit, Jamal
    Nuclear Medicine and Biology (1996), 23 (8), 957-980CODEN: NMBIEO; ISSN:0883-2897. (Elsevier)
    The chem., radiochem., radiobiol., and radiopharmacol. of radiopharmaceuticals contg. copper radionuclides are reviewed, with 210 refs. Copper radionuclides offer application in positron emission tomog., targeted radiotherapy, and single photon imaging. The chem. of copper is relatively simple and well-suited to radiopharmaceutical application. Current radiopharmaceuticals include biomols. labeled via bifunctional chelators primarily based on cyclic polyaminocarboxylates and polyamines, and pyruvaldehyde-bis(N4-methylthiosemicarbazone) (PTSM) and its analogs. The chem. of copper, of which only a fraction has yet been exploited, is likely to be applied more fully in the future.
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  38. 38
    Guo, Y.; Parry, J. J.; Laforest, R.; Rogers, B. E.; Anderson, C. J. The role of p53 in combination radioimmunotherapy with 64Cu–DOTA–cetuximab and cisplatin in a mouse model of colorectal cancer J. Nucl. Med. 2013, 54, 1621– 1629
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    There is no corresponding record for this reference.
  39. 39
    Donnelly, P. S. The role of coordination chemistry in the development of copper and rhenium radiopharmaceuticals Dalton Trans. 2011, 40, 999– 1010
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    There is no corresponding record for this reference.
  40. 40
    Smith, S. V. Molecular imaging with copper-64 J. Inorg. Biochem. 2004, 98, 1874– 1901
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    40
    Molecular imaging with copper-64
    Smith, Suzanne V.
    Journal of Inorganic Biochemistry (2004), 98 (11), 1874-1901CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier B.V.)
    A review. Mol. imaging is expected to change the face of drug discovery and development. The ability to link imaging to biol. for guiding therapy should improve the rate at which novel imaging technologies, probes, contrast agents, drugs and drug delivery systems can be transferred into clin. practice. Nuclear medicine imaging, in particular, positron emission tomog. (PET) allows the detection and monitoring of a variety of biol. and pathophysiol. processes, at tracer quantities of the radiolabeled target agents, and at doses free from pharmacol. effects. In the field of drug discovery and development, the use of radiotracers for radiolabelling target agents has now become one of the essential tools in identifying, screening and development of new target agents. In this regard, 64Cu (t1/2 = 12.7 h) has been identified as an emerging PET isotope. Its half-life is sufficiently long for radiolabelling a range of target agents and its ease of prodn. and adaptable chem. make it an excellent radioisotope for use in mol. imaging. This review describes recent advances, in the routes of 64Cu prodn., design and application of bi-functional ligands for use in radiolabelling with 64/67Cu2+, and their significance and anticipated impact on the field of mol. imaging and drug development.
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  41. 41
    Wadas, T. J.; Wong, E. H.; Weisman, G. R.; Anderson, C. J. Molecular imaging of cancer with copper-64 radiopharmaceuticals and positron emission tomography (PET) Chem. Rev. 2010, 110, 2858– 2902
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    41
    Coordinating Radiometals of Copper, Gallium, Indium, Yttrium, and Zirconium for PET and SPECT Imaging of Disease
    Wadas, Thaddeus J.; Wong, Edward H.; Weisman, Gary R.; Anderson, Carolyn J.
    Chemical Reviews (Washington, DC, United States) (2010), 110 (5), 2858-2902CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review.
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  42. 42
    Shokeen, M.; Anderson, C. J. Coordinating radiometals of copper, gallium, indium, yttrium, and zirconium for PET and SPECT imaging of disease Acc. Chem. Res. 2009, 110, 832– 841
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    There is no corresponding record for this reference.
  43. 43
    De Silva, R. A.; Peyre, K.; Pullambhatla, M.; Fox, J. J.; Pomper, M. G.; Nimmagadda, S. Imaging CXCR4 expression in human cancer xenografts: evaluation of monocyclam 64Cu–AMD3465 J. Nucl. Med. 2011, 52, 986– 993
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    There is no corresponding record for this reference.
  44. 44
    Yuan, H.; Schroeder, T.; Bowsher, J. E.; Hedlund, L. W.; Wong, T.; Dewhirst, M. W. Intertumoral differences in hypoxia selectivity of the PET imaging agent 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) J. Nucl. Med. 2006, 47, 989– 998
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    44
    Intertumoral differences in hypoxia selectivity of the PET imaging agent 64Cu(II)-diacetyl-Bis(N4-methylthiosemicarbazone)
    Yuan, Hong; Schroeder, Thies; Bowsher, James E.; Hedlund, Laurence W.; Wong, Terence; Dewhirst, Mark W.
    Journal of Nuclear Medicine (2006), 47 (6), 989-998CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)
    Cu-Diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) is a recently developed PET imaging agent for tumor hypoxia. However, its accuracy and reliability for measuring hypoxia have not been fully characterized in vivo. The aim of this study was to evaluate 64Cu-ATSM as a hypoxia PET marker by comparing autoradiog. distributions of 64Cu-ATSM with a well-established hypoxia marker drug, EF5. Methods: R3230 mammary adenocarcinomas (R3230Ac), fibrosarcomas (FSA), and 9L gliomas (9L) were used in the study. EF5 and Hoechst 33342, a vascular perfusion marker, were administered to the animal for immunohistochem. anal. 64Cu-ATSM microPET and autoradiog. were performed on the same animal. The tumor-to-muscle ratio (T/M ratio) and standardized uptake values (SUVs) were characterized for these 3 different types of tumors. Five types of images-microPET, autoradiog., EF5 immunostaining, Hoechst fluorescence vascular imaging, and hematoxylin-andeosin histol.-were superimposed, evaluated, and compared. Results: A significantly higher T/M ratio and SUV were seen for FSA compared with R3230Ac and 9L. Spatial correlation anal. between 64Cu-ATSM autoradiog. and EF5 immunostained images varied between the 3 tumor types. There was close correlation of 64Cu-ATSM uptake and hypoxia in R3230Ac and 9L tumors but not in FSA tumors. Interestingly, elevated 64Cu-ATSM uptake was obsd. in well-perfused areas in FSA, indicating a correlation between 64Cu-ATSM uptake and vascular perfusion as opposed to hypoxia. The same relationship was obsd. with 2 other hypoxia markers, pimonidazole and carbonic anhydrase IX, in FSA tumors. Breathing carbogen gas significantly decreased the hypoxia level measured by EF5 staining in FSA-bearing rats but not the uptake of 64Cu-ATSM. These results indicate that some other 64Cu-ATSM retention mechanisms, as opposed to hypoxia, are involved in this type of tumor. Conclusion: To our knowledge, this study is the first comparison between 64Cu-ATSM uptake and immunohistochem. in these 3 tumors. Although we have shown that 64Cu-ATSM is a valid PET hypoxia marker in some tumor types, but not for all, this tumor type-dependent hypoxia selectivity of 64Cu-ATSM challenges the use of 64Cu-ATSM as a universal PET hypoxia marker. Further studies are needed to define retention mechanisms for this PET marker.
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  45. 45
    Liu, Z.; Li, Z. B.; Cao, Q.; Liu, S.; Wang, F.; Chen, X. Small-animal PET of tumors with (64)Cu-labeled RGD–bombesin heterodimer J. Nucl. Med. 2009, 50, 1168– 1177
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    There is no corresponding record for this reference.
  46. 46
    Dumont, R. A.; Deininger, F.; Haubner, R.; Maecke, H. R.; Weber, W. A.; Fani, M. Novel (64)Cu- and (68)Ga-labeled RGD conjugates show improved PET imaging of alpha(nu)beta(3) integrin expression and facile radiosynthesis J. Nucl. Med. 2011, 52, 1276– 1284
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    There is no corresponding record for this reference.
  47. 47
    Fani, M.; Del Pozzo, L.; Abiraj, K.; Mansi, R.; Tamma, M. L.; Cescato, R.; Waser, B.; Weber, W. A.; Reubi, J. C.; Maecke, H. R. PET of somatostatin receptor-positive tumors using 64Cu– and 68Ga–somatostatin antagonists: the chelate makes the difference J. Nucl. Med. 2011, 52, 1110– 1118
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    47
    PET of somatostatin receptor-positive tumors using 64Cu- and 68Ga-somatostatin antagonists: the chelate makes the difference
    Fani, Melpomeni; Del Pozzo, Luigi; Abiraj, Keelara; Mansi, Rosalba; Tamma, Maria Luisa; Cescato, Renzo; Waser, Beatrice; Weber, Wolfgang A.; Reubi, Jean Claude; Maecke, Helmut R.
    Journal of Nuclear Medicine (2011), 52 (7), 1110-1118CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)
    Somatostatin-based radiolabeled peptides have been successfully introduced into the clinic for targeted imaging and radionuclide therapy of somatostatin receptor (sst)-pos. tumors, esp. of subtype 2 (sst2). The clin. used peptides are exclusively agonists. Recently, we showed that radiolabeled antagonists may be preferable to agonists because they showed better pharmacokinetics, including higher tumor uptake. Factors detg. the performance of radioantagonists have only scarcely been studied. Here, we report on the development and evaluation of four 64Cu or 68Ga radioantagonists for PET of sst2-pos. tumors. Methods: The novel antagonist p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2 (LM3) was coupled to 3 macrocyclic chelators, namely 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), 1,4,7-triazacyclononane, 1-glutaric acid-4,7-acetic acid (NODAGA), and DOTA. 64/natCu- and 68/natGa-NODAGA-LM3 were prepd. at room temp., and 64/natCu-CB-TE2A-LM3 and 68/natGa-DOTA-LM3 were prepd. at 95°C. Binding affinity and antagonistic properties were detd. with receptor autoradiog. and immunofluorescence microscopy using human embryonic kidney (HEK)-sst2 cells. In vitro internalization and dissocn. was evaluated using the same cell line. Biodistribution and small-animal PET studies were performed with HEK-sst2 xenografts. Results: All metallopeptides demonstrated antagonistic properties. The affinities depend on chelator and radiometal and vary about 10-fold; 68/natGa-NODAGA-LM3 has the lowest half maximal inhibitory concn. (1.3 ± 0.3 nmol/L). The biodistribution studies show impressive tumor uptake at 1 h after injection, particularly of 64Cu- and 68Ga-NODAGA-LM3 (∼40 percentage injected dose per g of tissue [%ID/g]), which were proven to be specific. Background clearance was fast and the tumor washout relatively slow for 64Cu-NODAGA-LM3 (∼15 %ID/g, 24 h after injection) and almost negligible for 64Cu-CB-TE2A-LM3 (26.9 ± 3.3 %ID/g and 21.6 ± 2.1 %ID/g, 4 and 24 h after injection, resp.). Tumor-to-normal-tissue ratios were significantly higher for 64Cu-NODAGA-LM3 than for 64Cu-CB-TE2A-LM3 (tumor-to-kidney, 12.8 ± 3.6 and 1.7 ± 0.3, resp.; tumor-to-muscle, 1,342 ± 115 and 75.2 ± 8.5, resp., at 24 h, P < 0.001). Small-animal PET shows clear tumor localization and high image contrast, esp. for 64Cu- and 68Ga-NODAGA-LM3. Conclusion: This article demonstrates the strong dependence of the affinity and pharmacokinetics of the somatostatin-based radioantagonists on the chelator and radiometal. 64Cu- and 68Ga-NODAGA-LM3 and 64Cu-CB-TE2A-LM3 are promising candidates for clin. translation because of their favorable pharmacokinetics and the high image contrast on PET scans.
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  48. 48
    Liu, Z.; Li, Z. B.; Cao, Q.; Liu, S.; Wang, F.; Chen, X.; Small-animal, P. E. T. of tumors with (64)Cu-labeled RGD–bombesin heterodimer J. Nucl. Med. 2009, 50, 1168– 1177
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    There is no corresponding record for this reference.
  49. 49
    Rockey, W. M.; Huang, L.; Kloepping, K. C.; Baumhover, N. J.; Giangrande, P. H.; Schultz, M. K. Synthesis and radiolabeling of chelator–RNA aptamer bioconjugates with copper-64 for targeted molecular imaging Bioorg. Med. Chem. 2011, 19, 4080– 4090
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    There is no corresponding record for this reference.
  50. 50
    Hou, G. L.; Li, Y. H.; Zhang, Z. L.; Xiong, Y. H.; Chen, X. F.; Yao, K.; Liu, Z. W.; Han, H.; Qin, Z. K.; Zhou, F. J. A modified technique for neourethral anastomosis in orthotopic neobladder reconstruction Urology 2009, 74, 1145– 1149
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    There is no corresponding record for this reference.
  51. 51
    Cooper, M. S.; Ma, M. T.; Sunassee, K.; Shaw, K. P.; Williams, J. D.; Paul, R. L.; Donnelly, P. S.; Blower, P. J. Comparison of (64)Cu-complexing bifunctional chelators for radioimmunoconjugation: labeling efficiency, specific activity, and in vitro/in vivo stability Bioconjugate Chem. 2012, 23, 1029– 1039
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    51
    Comparison of 64Cu-Complexing Bifunctional Chelators for Radioimmunoconjugation: Labeling Efficiency, Specific Activity, and in Vitro/in Vivo Stability
    Cooper, Maggie S.; Ma, Michelle T.; Sunassee, Kavitha; Shaw, Karen P.; Williams, Jennifer D.; Paul, Rowena L.; Donnelly, Paul S.; Blower, Philip J.
    Bioconjugate Chemistry (2012), 23 (5), 1029-1039CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    High radiolabeling efficiency, preferably to high specific activity, and good stability of the radioimmunoconjugate are essential features for a successful immunoconjugate for imaging or therapy. In this study, the radiolabeling efficiency, in vitro stability, and biodistribution of immunoconjugates with eight different bifunctional chelators labeled with 64Cu were compared. The anti-CD20 antibody, rituximab, was conjugated to four macrocyclic bifunctional chelators (p-SCN-Bn-DOTA, p-SCN-Bn-Oxo-DO3A, p-SCN-NOTA, and p-SCN-PCTA), three DTPA derivs. (p-SCN-Bn-DTPA, p-SCN-CHX-A''-DTPA, and ITC-2B3M-DTPA), and a macrobicyclic hexamine (sarcophagine) chelator (sar-CO2H) = (1-NH2-8-NHCO(CH2)3CO2H)sar where sar = sarcophagine = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane. Radiolabeling efficiency under various conditions, in vitro stability in serum at 37 °C, and in vivo biodistribution and imaging in normal mice over 48 h were studied. All chelators except sar-CO2H were conjugated to rituximab by thiourea bond formation with an av. of 4.9 ± 0.9 chelators per antibody mol. Sar-CO2H was conjugated to rituximab by amide bond formation with 0.5 chelators per antibody mol. Efficiencies of 64Cu radiolabeling were dependent on the concn. of immunoconjugate. Notably, the 64Cu-NOTA-rituximab conjugate demonstrated the highest radiochem. yield (95%) under very dil. conditions (31 nM NOTA-rituximab conjugate). Similarly, sar-CO-rituximab, contg. 1/10th the no. of chelators per antibody compared to that of other conjugates, retained high labeling efficiency (98%) at an antibody concn. of 250 nM. In contrast to the radioimmunoconjugates contg. DTPA derivs., which demonstrated poor serum stability, all macrocyclic radioimmunoconjugates were very stable in serum with <6% dissocn. of 64Cu over 48 h. In vivo biodistribution profiles in normal female Balb/C mice were similar for all the macrocyclic radioimmunoconjugates with most of the activity remaining in the blood pool up to 48 h. While all the macrocyclic bifunctional chelators are suitable for mol. imaging using 64Cu-labeled antibody conjugates, NOTA and sar-CO2H show significant advantages over the others in that they can be radiolabeled rapidly at room temp., under dil. conditions, resulting in high specific activity.
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  52. 52
    Moi, M. K.; Meares, C. F.; McCall, M. J.; Cole, W. C.; DeNardo, S. J. Copper chelates as probes of biological systems: stable copper complexes with a macrocyclic bifunctional chelating agent Anal. Biochem. 1985, 148, 249– 253
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    Copper chelates as probes of biological systems: stable copper complexes with a macrocyclic bifunctional chelating agent
    Moi, Min K.; Meares, Claude F.; McCall, Michael J.; Cole, William C.; DeNardo, Sally J.
    Analytical Biochemistry (1985), 148 (1), 249-53CODEN: ANBCA2; ISSN:0003-2697.
    The synthesis of a new bifunctional metal chelator, 6-(p-bromoacetamidobenzyl)-1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA) is described, which can be covalently attached to proteins and which binds Cu stably in human serum under physiol. conditions. 67Cu chelates of p-nitrobenzyl-TETA, p-nitrobenzyl-EDTA, diethylenetriaminepentaacetic acid (DTPA)-N-butylamide, and DTPA, as well as conjugates of Cu chelates with mouse monoclonal antibody lym-1 were also prepd. and their stability in human serum was examd. In contrast to TETA, Cu chelates prepd. from analogs of EDTA or DTPA were not stable to prolonged incubation in human serum and rapidly lost Cu to serum albumin.
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  53. 53
    Jones-Wilson, T. M.; Deal, K. A.; Anderson, C. J.; McCarthy, D. W.; Kovacs, Z.; Motekaitis, R. J.; Sherry, A. D.; Martell, A. E.; Welch, M. J. The in vivo behavior of copper-64-labeled azamacrocyclic complexes Nucl. Med. Biol. 1998, 25, 523– 530
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    53
    The in vivo behavior of copper-64-labeled azamacrocyclic complexes
    Jones-Wilson, Teresa M.; Deal, Kim A.; Anderson, Carolyn J.; McCarthy, Deborah W.; Kovacs, Zoltan; Motekaitis, Ramunas J.; Sherry, A. Dean; Martell, Arthur E.; Welch, Michael J.
    Nuclear Medicine and Biology (1998), 25 (6), 523-530CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Science Inc.)
    The use of copper radioisotopes in imaging and therapy applications has created a greater need for bifunctional chelates (BFCs) for complexing copper radioisotopes to biomols. It has been demonstrated that the charge and lipophilicity of the Cu-BFC complex has a significant effect on the in vivo behavior of the radiolabeled Cu-BFC-biomol. conjugate. To evaluate the effects of charge, stability, and macrocyclic backbone size on the biol. behavior of 64Cu complexes, a series of macrocyclic 64Cu complexes have been prepd., and the biodistributions of these agents were evaluated in normal Sprague-Dawley rats. Two macrocyclic backbones, dodecane and tetradecane, were evaluated; cyclen, DOTA, and DO2A were dodecane backbone derivs., and cyclam, TETA, and et-cyclam were tetradecane backbone derivs. The biodistributions of the 64Cu-labeled complexes correlated with differences in the size of the macrocycle backbone and the formal charge of the complex. All compds. showed uptake and clearance through the liver and kidneys; however, the pos. charged 64Cu complexes showed significantly higher uptake in both of these organs than did the neg. charged or neutral complexes. 64Cu-TETA, a neg. charged complex with the tetradecane backbone, had the most efficient clearance by 24 h' postinjection. These data suggest that neg. charged complexes may have more favorable clearance properties when used as BFCs.
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  54. 54
    Garrison, J. C.; Rold, T. L.; Sieckman, G. L.; Figueroa, S. D.; Volkert, W. A.; Jurisson, S. S.; Hoffman, T. J. In vivo evaluation and small-animal PET/CT of a prostate cancer mouse model using 64Cu bombesin analogs: side-by-side comparison of the CB-TE2A and DOTA chelation systems J. Nucl. Med. 2007, 48, 1327– 1337
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    54
    In vivo evaluation and small-animal PET/CT of a prostate cancer mouse model using 64Cu bombesin analogs: side-by-side comparison of the CB-TE2A and DOTA chelation systems
    Garrison, Jered C.; Rold, Tammy L.; Sieckman, Gary L.; Figueroa, Said Daibes; Volkert, Wynn A.; Jurisson, Silvia S.; Hoffman, Timothy J.
    Journal of Nuclear Medicine (2007), 48 (8), 1327-1337CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)
    The BB2 receptor subtype, of the bombesin family of receptors, has been shown to be highly overexpressed in a variety of human tumors, including prostate cancer. Bombesin (BBN), a 14-amino acid peptide, has been shown to target the BB2 receptor with high affinity. 64Cu (half-life = 12.7 h, β+: 18%, Eβ+max = 653 keV; β-: 37%, Eβ-max = 578 keV) is a radioisotope that has clin. potential for application in both diagnostic imaging and radionuclide therapy. Recently, new chelation systems such as 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A) have been reported to significantly stabilize the 64Cu radiometal in vivo. The increased stability of the 64Cu-CB-TE2A chelate complex has been shown to significantly reduce nontarget retention compared with tetraazamacrocycles such as 1,4,7,10-tetraazacyclodoadecane-N,N',N",N'"-tetraacetic acid (DOTA). The aim of this study was to det. whether the CB-TE2A chelation system could significantly improve the in vivo stability of 64Cu bombesin analogs. The study directly compares 64Cu bombesin analogs using the CB-TE2A and DOTA chelation systems in a prostate cancer xenograft SCID (severely compromised immunodeficient) mouse model. Methods: The CB-TE2A-8-AOC-BBN(7-14)NH2 and DOTA-8-AOC-BBN(7-14) NH2 conjugates were synthesized and radiolabeled with 64Cu. The receptor-binding affinity and internalization profile of each metalated conjugate was evaluated using PC-3 cells. Pharmacokinetic and small-animal PET/CT studies were performed using female SCID mice bearing PC-3 xenografts. Results: In vivo BB2 receptor targeting was confirmed by tumor uptake values of 6.95 ± 2.27 and 4.95 ± 0.91 %ID/g (percentage injected dose per g) at the 15-min time point for the 64Cu-CB-TE2A and 64Cu-DOTA radioconjugates, resp. At the 24-h time point, liver uptake was substantially reduced for the 64Cu-CB-TE2A radioconjugate (0.21 ± 0.06 %ID/g) compared with the 64Cu-DOTA radioconjugate (7.80 ± 1.51 %ID/g). The 64Cu-CB-TE2A-8-AOC-BBN(7-14)NH2 radioconjugate demonstrated significant clearance, 98.60 ± 0.28 %ID, from the mouse at 24 h after injection. In contrast, only 67.84 ± 5.43 %ID of the 64Cu activity was excreted using the 64Cu-DOTA-8-AOC-BBN(7-14)NH2 radioconjugate because of nontarget retention. Conclusion: The pharmacokinetic and small-animal PET/CT studies demonstrate significantly improved nontarget tissue clearance for the 64Cu-CB-TE2A8-AOC-BBN(7-14)NH2. This is attributed to the improved in vivo stability of the 64Cu-CB-TE2A chelate complex as compared with the 64Cu-DOTA chelate complex.
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    Sun, X.; Wuest, M.; Weisman, G. R.; Wong, E. H.; Reed, D. P.; Boswell, C. A.; Motekaitis, R.; Martell, A. E.; Welch, M. J.; Anderson, C. J. Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands J. Med. Chem. 2002, 45, 469– 477
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    Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands
    Sun, Xiankai; Wuest, Melinda; Weisman, Gary R.; Wong, Edward H.; Reed, David P.; Boswell, C. Andrew; Motekaitis, Ramunas; Martell, Arthur E.; Welch, Michael J.; Anderson, Carolyn J.
    Journal of Medicinal Chemistry (2002), 45 (2), 469-477CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Macrocyclic chelators and their metal complexes have widespread applications in the biomedical sciences, including radiopharmaceutical chem. The use of copper radionuclides in radiopharmaceuticals is increasing. Macrocyclic chelators have been found to have enhanced in vivo stability over acyclic chelators such as EDTA and diethylenetriaminepentaacetic acid (DTPA). The currently used chelators of choice for labeling copper radionuclides to biol. mols. are analogs of TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid); however, recent reports have demonstrated evidence of in vivo instability of the radio-Cu(II)-TETA complexes. A new class of structurally reinforced macrocycles, the "cross-bridged" cyclam derivs., form highly stable complexes with Cu(II) that are resistant to dissocn. in strong acid. Here, we evaluate a series of 64Cu(II) cross-bridged macrocyclic complexes for biol. stability and in vivo behavior. The ligands evaluated include the parent ligand, 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (1), and three 4,11-di-pendant arm derivs.: 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (2); 4,11-bis(N,N-diethyl-amidomethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (3); and 4,11-bis(amidoethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (4). Copper-64 formed complexes with ligands 1-4 in high radiochem. yields. The 64Cu-2 complex was neutral, while 64Cu complexes of 1, 3, and 4 were pos. charged. All complexes showed no decompn. in rat serum out to 24 h. Biodistribution expts. in Sprague-Dawley rats indicated that 64Cu-1, -3, and -4 were taken up by the liver and kidney and cleared slowly over 24 h, whereas 64Cu-2 cleared rapidly from all tissues. The rapid clearance of the 64Cu-2 complex from the blood and liver, as well as liver metab. expts. in rats, suggests that it is highly stable in vivo. A bifunctional chelator of 2 is a significant candidate for labeling copper radionuclides to biol. mols. for diagnostic imaging and targeted radiotherapy.
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    Boswell, C. A.; Sun, X.; Niu, W.; Weisman, G. R.; Wong, E. H.; Rheingold, A. L.; Anderson, C. J. Comparative in vivo stability of copper-64-labeled cross-bridged and conventional tetraazamacrocyclic complexes J. Med. Chem. 2004, 47, 1465– 1474
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    56
    Comparative in Vivo Stability of Copper-64-Labeled Cross-Bridged and Conventional Tetraazamacrocyclic Complexes
    Boswell, C. Andrew; Sun, Xiankai; Niu, Weijun; Weisman, Gary R.; Wong, Edward H.; Rheingold, Arnold L.; Anderson, Carolyn J.
    Journal of Medicinal Chemistry (2004), 47 (6), 1465-1474CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The increased use of copper radioisotopes in radiopharmaceutical applications has created a need for bifunctional chelators (BFCs) that form stable radiocopper complexes and allow covalent attachment to biol. mols. The chelators most commonly utilized for labeling copper radionuclides to biomols. are analogs of 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); however, recent reports have communicated the instability of the radio-Cu(II)-TETA complexes in vivo. A class of bicyclic tetraazamacrocycles, the ethylene "cross-bridged" cyclam (CB-cyclam) derivs., form highly kinetically stable complexes with Cu(II) and therefore may be less susceptible to transchelation than their nonbridged analogs in vivo. Herein we report results on the relative biol. stabilities and identification of the resulting radiolabeled metabolites of a series of 64Cu-labeled macrocyclic complexes. Metab. studies in normal rat liver have revealed that the 64Cu complex of 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (64Cu-CB-TE2A) resulted in significantly lower values of protein-assocd. 64Cu than 64Cu-TETA [13 ± 6% vs 75 ± 9% at 4 h]. A similar trend was obsd. for the corresponding cyclen derivs., with the 64Cu complex of 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (64Cu-CB-DO2A) undergoing less transchelation than the 64Cu complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (64Cu-DOTA) [61 ± 14% vs 90.3 ± 0.5% protein assocd. 64Cu at 4 h]. These data indicate that the structurally reinforcing cross-bridge enhances in vivo stability by reducing metal loss to protein in both the cyclam and cyclen cross-bridged 64Cu complexes and that 64Cu-CB-TE2A is superior to 64Cu-CB-DO2A in that regard. These findings further suggest that a bifunctional chelator deriv. of CB-TE2A is a highly desirable alternative for labeling copper radionuclides to biol. mols. for diagnostic imaging and targeted radiotherapy.
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  57. 57
    Sprague, J. E.; Peng, Y.; Sun, X.; Weisman, G. R.; Wong, E. H.; Achilefu, S.; Anderson, C. J. Preparation and biological evaluation of copper-64-labeled tyr3-octreotate using a cross-bridged macrocyclic chelator Clin. Cancer Res. 2004, 10, 8674– 8682
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    57
    Preparation and biological evaluation of copper-64-labeled Tyr3-octreotate using a cross-bridged macrocyclic chelator
    Sprague, Jennifer E.; Peng, Yijie; Sun, Xiankai; Weisman, Gary R.; Wong, Edward H.; Achilefu, Samuel; Anderson, Carolyn J.
    Clinical Cancer Research (2004), 10 (24), 8674-8682CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
    Somatostatin receptors (SSTr) are expressed on many neuroendocrine tumors, and several radiotracers have been developed for imaging these types of tumors. For this reason, peptide analogs of somatostatin have been well characterized. Copper-64 (t1/2 = 12.7 h), a positron emitter suitable for positron emission tomog. (PET) imaging, was shown recently to have improved in vivo clearance properties when chelated by the cross-bridged tetraazamacrocycle 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane (CB-TE2A) compared with 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA). CB-TE2A and TETA were conjugated to the somatostatin analog tyrosine-3-octreotate (Y3-TATE) for evaluation of CB-TE2A as a bifunctional chelator of 64Cu. The in vitro affinity of each compd. for SSTr was detd. using a homologous competitive binding assay. In vivo characteristics of both radiolabeled compds. were examd. in biodistribution and microPET studies of AR42J tumor-bearing rats. Cu-CB-TE2A-Y3-TATE (Kd = 1.7 nmol/L) and Cu-TETA-Y3-TATE (Kd = 0.7 nmol/L) showed similar affinities for AR42J derived SSTr. In biodistribution studies, nonspecific uptake in blood and liver was lower for 64Cu-CB-TE2A-Y3-TATE. Differences increased with time such that, at 4 h, blood uptake was 4.3-fold higher and liver uptake was 2.4-fold higher for 64Cu-TETA-Y3-TATE than for 64Cu-CB-TE2A-Y3-TATE. In addn., 4.4-times greater tumor uptake was detected with 64Cu-CB-TE2A-Y3-TATE than with 64Cu-TETA-Y3-TATE at 4 h postinjection. MicroPET imaging yielded similar results. CB-TE2A appears to be a superior in vivo bifunctional chelator of 64Cu for use in mol. imaging by PET or targeted radiotherapy due to both improved nontarget organ clearance and higher target organ uptake of 64Cu-CB-TE2A-Y3-TATE compared with 64Cu-TETA-Y3-TATE.
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  58. 58
    Ait-Mohand, S.; Fournier, P.; Dumulon-Perreault, V.; Kiefer, G. E.; Jurek, P.; Ferreira, C. L.; Benard, F.; Guerin, B. Evaluation of 64Cu-labeled bifunctional chelate–bombesin conjugates Bioconjugate Chem. 2011, 22, 1729– 1735
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    58
    Evaluation of 64Cu-Labeled Bifunctional Chelate-Bombesin Conjugates
    Ait-Mohand, Samia; Fournier, Patrick; Dumulon-Perreault, Veronique; Kiefer, Garry E.; Jurek, Paul; Ferreira, Cara L.; Benard, Francois; Guerin, Brigitte
    Bioconjugate Chemistry (2011), 22 (8), 1729-1735CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    Several bifunctional chelates (BFCs) were investigated as carriers of 64Cu for PET imaging. The most widely used chelator for 64Cu labeling of BFCs is DOTA (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tretraacetic acid), even though this complex exhibits only moderate in vivo stability. In this study, we prepd. a series of alternative chelator-peptide conjugates labeled with 64Cu, measured in vitro receptor binding affinities in human breast cancer T47D cells expressing the gastrin-releasing peptide receptor (GRPR) and compared their in vivo stability in mice. DOTA-, NOTA-(1,4,7-triazacyclononane-1,4,7-triacetic acid), PCTA-(3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid), and Oxo-DO3A-(1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid) peptide conjugates were prepd. using H2N-Aoc-[D-Tyr6,βAla11,Thi13,Nle14]bombesin(6-14) (BBN) as a peptide template. The BBN moiety was selected since it binds with high affinity to the GRPR, which is overexpressed on human breast cancer cells. A convenient synthetic approach for the attachment of aniline-BFC to peptides on solid support is also presented. To facilitate the attachment of the aniline-PCTA and aniline-Oxo-DO3A to the peptide via an amide bond, a succinyl spacer was introduced at the N-terminus of BBN. The partially protected aniline-BFC (p-H2N-Bn-PCTA(Ot-Bu)3 or p-H2N-Bn-DO3A(Ot-Bu)3) was then coupled to the resulting N-terminal carboxylic acid preactivated with DEPBT/ClHOBt on resin. After cleavage and purifn., the peptide-conjugates were labeled with 64Cu using [64Cu]Cu(OAc)2 in 0.1 M ammonium acetate buffer at 100 °C for 15 min. Labeling efficacy was >90% for all peptides; Oxo-DO3A-BBN was incubated an addnl. 150 min at 100 °C to achieve this high yield. Specific activities varied from 76 to 101 TBq/mmol. Competition assays on T47D cells showed that all BFC-BBN complexes retained high affinity for the GRPR. All BFC-BBN 64Cu-conjugates were stable for over 20 h when incubated at 37 °C in mouse plasma samples. However, in vivo, only 37% of the 64Cu/Oxo-DO3A complex remained intact after 20 h while the 64Cu/DOTA-BBN complex was completely demetalated. In contrast, both 64Cu/NOTA- and 64Cu/PCTA-BBN conjugates remained stable during the 20 h time period. Our results indicate that it is possible to successfully conjugate aniline-BFC with peptide on solid support. Our data also show that 64Cu-labeled NOTA- and PCTA-BBN peptide conjugates are promising radiotracers for PET imaging of many human cancers overexpressing the GRP receptor.
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    Ferreira, C. L.; Lamsa, E.; Woods, M.; Duan, Y.; Fernando, P.; Bensimon, C.; Kordos, M.; Guenther, K.; Jurek, P.; Kiefer, G. E. Evaluation of Bifunctional Chelates for the Development of Gallium-Based Radiopharmaceuticals Bioconjugate Chem. 2010, 21, 531– 536
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    59
    Evaluation of Bifunctional Chelates for the Development of Gallium-Based Radiopharmaceuticals
    Ferreira, Cara L.; Lamsa, Eric; Woods, Michael; Duan, Yin; Fernando, Pasan; Bensimon, Corinne; Kordos, Myra; Guenther, Katharina; Jurek, Paul; Kiefer, Garry E.
    Bioconjugate Chemistry (2010), 21 (3), 531-536CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    Ga radioisotopes, including the generator-produced positron-emitting isotope 68Ga (t1/2 = 68 min), are of increasing interest for the development of new radiopharmaceuticals. Bifunctional chelates (BFCs) that can be efficiently radiolabeled with Ga to yield complexes with good in vivo stability are needed. To this end, we undertook a systematic comparison of four BFCs contg. different chelating moieties: two novel BFCs, p-NO2-Bn-Oxo (1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid) and p-NO2-Bn-PCTA (3,6,9,15-tetraazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid), and two more commonly used BFCs, p-NO2-Bn-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and p-NO2-Bn-NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid). Each BFC was compared with respect to radiolabeling conditions, radiochem. yield, stability, and in vivo clearance properties. p-NO2-Bn-PCTA, p-NO2-Bn-Oxo, and p-NO2-Bn-NOTA were all more efficiently radiolabeled with Ga compared to p-NO2-Bn-DOTA. p-NO2-Bn-DOTA required longer reaction time, higher concns. of BFC, or heating to obtain equiv. radiochem. yields. Better stability was obsd. for p-NO2-Bn-NOTA and p-NO2-Bn-PCTA compared to p-NO2-Bn-DOTA and p-NO2-Bn-Oxo, esp. with respect to transmetalation to transferrin. Ga-radiolabled p-NO2-Bn-Oxo was found to be kinetically labile and therefore unstable in vivo. Ga-radiolabeled p-NO2-Bn-NOTA and p-NO2-Bn-PCTA were relatively inert, while Ga-radiolabeled p-NO2-Bn-DOTA had intermediate stability, losing >20% of Ga in less than one hour when incubated with apo-transferrin. Similar stability differences were seen when incubating at pH 2. In vivo PET imaging and biodistribution studies in mice showed that 68Ga-radiolabeled p-NO2-Bn-PCTA, p-NO2-Bn-NOTA, and p-NO2-Bn-DOTA all cleared through the kidneys. While there was no statistical difference in the biodistribution results of 68Ga-radiolabeled p-NO2-Bn-PCTA and p-NO2-Bn-DOTA, 68Ga-radiolabeled p-NO2-Bn-NOTA cleared more rapidly from blood and muscle tissue but retained at up to 5 times higher activity in the kidneys.
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  60. 60
    Ferreira, C. L.; Yapp, D. T.; Lamsa, E.; Gleave, M.; Bensimon, C.; Jurek, P.; Kiefer, G. E. Evaluation of novel bifunctional chelates for the development of Cu-64-based radiopharmaceuticals Nucl. Med. Biol. 2008, 35, 875– 882
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    60
    Evaluation of novel bifunctional chelates for the development of Cu-64-based radiopharmaceuticals
    Ferreira, Cara L.; Yapp, Donald T.; Lamsa, Eric; Gleave, Martin; Bensimon, Corinne; Jurek, Paul; Kiefer, Garry E.
    Nuclear Medicine and Biology (2008), 35 (8), 875-882CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)
    Background: Currently available bifunctional chelates (BFCs) for attaching Cu-64 to a targeting mol. are limited by either their radiolabeling conditions or in vivo stability. With the goal of identifying highly effective BFCs, we compared the properties of two novel BFCs, 1-oxa-4,7,10-triazacyclododecane-S-5-(4-nitrobenzyl)-4,7,10-triacetic acid (p-NO2-Bn-Oxo) and 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-S-4-(4-nitrobenzyl)-3,6,9-triacetic acid (p-NO2-Bn-PCTA), with the commonly used S-2-(4-nitrobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid (p-NO2-Bn-DOTA). Methods: p-NO2-Bn-DOTA, p-NO2-Bn-Oxo and p-NO2-Bn-PCTA were each radiolabeled with Cu-64 under various conditions to assess the reaction kinetics and robustness of the radiolabeling. Stability of each Cu-64 BFC complex was evaluated at low pH and in serum. Small animal positron emission tomog. imaging and biodistribution studies in mice were undertaken. Results: p-NO2-Bn-Oxo and p-NO2-Bn-PCTA possessed superior reaction kinetics compared to p-NO2-Bn-DOTA under all radiolabeling conditions; >98% radiochem. yields were achieved in <5 min at room temp. even when using near stoichiometric amts. of BFC. Under nonideal conditions, such as low or high pH, high radiochem. yields were still achievable with the novel BFCs. The radiolabeled compds. were stable in serum and at pH 2 for 48 h. The imaging and biodistribution of the Cu-64-radiolabeled BFCs illustrated differences between the BFCs, including preferential clearance via the kidneys for the p-NO2-Bn-PCTA Cu-64 complex. Conclusions: The novel BFCs facilitated efficient Cu-64 radiolabeling under mild conditions to produce stable complexes at potentially high specific activities. These BFCs may find wide utility in the development of Cu-64-based radiopharmaceuticals.
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  61. 61
    Olszewski, R. T.; Bukhari, N.; Zhou, J.; Kozikowski, A. P.; Wroblewski, J. T.; Shamimi-Noori, S.; Wroblewska, B.; Bzdega, T.; Vicini, S.; Barton, F. B.; Neale, J. H. NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR J. Neurochem. 2004, 89, 876– 885
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    NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR
    Olszewski, Rafal T.; Bukhari, Noreen; Zhou, Jia; Kozikowski, Alan P.; Wroblewski, Jarda T.; Shamimi-Noori, Susan; Wroblewska, Barbara; Bzdega, Tomasz; Vicini, Stefano; Barton, Franca B.; Neale, Joseph H.
    Journal of Neurochemistry (2004), 89 (4), 876-885CODEN: JONRA9; ISSN:0022-3042. (Blackwell Publishing Ltd.)
    Phencyclidine (PCP) administration elicits pos. and neg. symptoms that resemble those of schizophrenia and is widely accepted as a model for the study of this human disorder. Group II metabotropic glutamate receptor (mGluR) agonists have been reported to reduce the behavioral and neurochem. effects of PCP. The peptide neurotransmitter, N-acetylaspartylglutamate (NAAG), is a selective group II agonist. The authors synthesized and characterized a urea-based NAAG analog, ZJ43. This novel compd. is a potent inhibitor of enzymes, glutamate carboxypeptidase II (Ki = 0.8 nM) and III (Ki = 23 nM) that deactivate NAAG following synaptic release. ZJ43 (100 μM) does not directly interact with NMDA receptors or metabotropic glutamate receptors. Administration of ZJ43 significantly reduced PCP-induced motor activation, falling while walking, stereotypic circling behavior, and head movements. To test the hypothesis that this effect of ZJ43 was mediated by increasing the activation of mGluR3 via increased levels of extracellular NAAG, the group II mGluR selective antagonist LY341495 was co-administered with ZJ43 prior to PCP treatment. This antagonist completely reversed the effects of ZJ43. Addnl., LY341495 alone increased PCP-induced motor activity and head movements suggesting that normal levels of NAAG act to moderate the effect of PCP on motor activation via a group II mGluR. These data support the view that NAAG peptidase inhibitors may represent a new therapeutic approach to some of the components of schizophrenia that are modeled by PCP.
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  62. 62
    Silver, D. A.; Pellicer, I.; Fair, W. R.; Heston, W. D.; Cordon-Cardo, C. Prostate-specific membrane antigen expression in normal and malignant human tissues Clin. Cancer Res. 1997, 3, 81– 95
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    62
    Prostate-specific membrane antigen expression in normal and malignant human tissues
    Silver D A; Pellicer I; Fair W R; Heston W D; Cordon-Cardo C
    Clinical cancer research : an official journal of the American Association for Cancer Research (1997), 3 (1), 81-5 ISSN:1078-0432.
    Prostate-specific membrane antigen is a type II membrane protein with folate hydrolase activity produced by prostatic epithelium. The expression of this molecule has also been documented in extraprostatic tissues, including small bowel and brain. In the present study, an extensive immunohistochemical analysis was performed on a panel of well-characterized normal and malignant human tissues to further define the pattern of prostate-specific membrane antigen (PSMA) expression. Detectable PSMA levels were identified in prostatic epithelium, duodenal mucosa, and a subset of proximal renal tubules. A subpopulation of neuroendocrine cells in the colonic crypts also exhibited PSMA immunoreactivity. All other normal tissues, including cerebral cortex and cerebellum, had undetectable levels of PSMA. Thirty-three of 35 primary prostate adenocarcinomas and 7 of 8 lymph node metastases displayed tumor cell PSMA immunostaining. Eight of 18 prostate tumors metastatic to bone expressed PSMA. All of the other nonprostatic primary tumors studied had undetectable PSMA levels. However, intense staining was observed in endothelial cells of capillary vessels in peritumoral and endotumoral areas of certain malignancies, including 8 of 17 renal cell carcinomas, 7 of 13 transitional cell carcinomas, and 3 of 19 colon carcinomas. Extraprostatic PSMA expression appears to be highly restricted. Nevertheless, its diverse anatomical distribution implies a broader functional significance than previously suspected. The decrease in PSMA immunoreactivity noted in advanced prostate cancer suggests that expression of this molecule may be linked to the degree of tumor differentiation. The neoexpression of PSMA in endothelial cells of capillary beds in certain tumors may be related to tumor angiogenesis and suggests a potential mechanism for specific targeting of tumor neovasculature.
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  63. 63
    Prasanphanich, A. F.; Nanda, P. K.; Rold, T. L.; Ma, L.; Lewis, M. R.; Garrison, J. C.; Hoffman, T. J.; Sieckman, G. L.; Figueroa, S. D.; Smith, C. J. [64Cu-NOTA-8-Aoc-BBN(7–14)NH2] targeting vector for positron-emission tomography imaging of gastrin-releasing peptide receptor-expressing tissues Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 12462– 12467
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  64. 64
    Chen, Y.; Pullambhatla, M.; Foss, C. A.; Byun, Y.; Nimmagadda, S.; Senthamizhchelvan, S.; Sgouros, G.; Mease, R. C.; Pomper, M. G. 2-(3-{1-Carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pen tanedioic acid, [18F]DCFPyL, a PSMA-based PET imaging agent for prostate cancer Clin. Cancer Res. 2011, 17, 7645– 7653
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    64
    2-(3-{1-Carboxy-5-[(6-[18F]Fluoro-Pyridine-3-Carbonyl)-Amino]-Pentyl}-Ureido)-Pentanedioic Acid, [18F]DCFPyL, a PSMA-Based PET Imaging Agent for Prostate Cancer
    Chen, Ying; Pullambhatla, Mrudula; Foss, Catherine A.; Byun, Youngjoo; Nimmagadda, Sridhar; Senthamizhchelvan, Srinivasan; Sgouros, George; Mease, Ronnie C.; Pomper, Martin G.
    Clinical Cancer Research (2011), 17 (24), 7645-7653CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
    PURPOSE: We have synthesized and evaluated in vivo 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid, [18F]DCFPyL, as a potential imaging agent for the prostate-specific membrane antigen (PSMA). PSMA is upregulated in prostate cancer epithelia and in the neovasculature of most solid tumors. Exptl. Design: [18F]DCFPyL was synthesized in two steps from the p-methoxybenzyl (PMB) protected lys-C(O)-glu urea precursor using 6-[18F]fluoronicotinic acid tetrafluorophenyl ester ([18F]F-Py-TFP) for introduction of 18F. Radiochem. synthesis was followed by biodistribution and imaging with PET in immunocompromised mice using isogenic PSMA PC3 PIP and PSMA- PC3 flu xenograft models. Human radiation dosimetry ests. were calcd. using OLINDA/EXM 1.0. RESULTS: DCFPyL displays a Ki value of 1.1 ± 0.1 nmol/L for PSMA. [18F]DCFPyL was produced in radiochem. yields of 36%-53% (decay cor.) and specific radioactivities of 340-480 Ci/mmol (12.6-17.8 GBq/μmol, n = 3). In an immunocompromised mouse model [18F]DCFPyL clearly delineated PSMA+ PC3 PIP prostate tumor xenografts on imaging with PET. At 2 h postinjection, 39.4 ± 5.4 percent injected dose per g of tissue (%ID/g) was evident within the PSMA+ PC3 PIP tumor, with a ratio of 358:1 of uptake within PSMA+ PC3 PIP to PSMA- PC3 flu tumor placed in the opposite flank. At or after 1 h postinjection, minimal nontarget tissue uptake of [18F]DCFPyL was obsd. The bladder wall is the dose-limiting organ. CONCLUSIONS: These data suggest [18F]DCFPyL as a viable, new positron-emitting imaging agent for PSMA-expressing tissues. Clin Cancer Res; 17(24); 7645-53.
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  65. 65
    Hillier, S. M.; Maresca, K. P.; Lu, G.; Merkin, R. D.; Marquis, J. C.; Zimmerman, C. N.; Eckelman, W. C.; Joyal, J. L.; Babich, J. W. 99mTc-Labeled Small-Molecule Inhibitors of Prostate-Specific Membrane Antigen for Molecular Imaging of Prostate Cancer J. Nucl. Med. 2013, 54, 1369– 1376
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  66. 66
    Elsasser-Beile, U.; Reischl, G.; Wiehr, S.; Buhler, P.; Wolf, P.; Alt, K.; Shively, J.; Judenhofer, M. S.; Machulla, H. J.; Pichler, B. J. PET imaging of prostate cancer xenografts with a highly specific antibody against the prostate-specific membrane antigen J. Nucl. Med. 2009, 50, 606– 611
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    66
    PET imaging of prostate cancer xenografts with a highly specific antibody against the prostate-specific membrane antigen
    Elsasser-Beile Ursula; Reischl Gerald; Wiehr Stefan; Buhler Patrick; Wolf Philipp; Alt Karen; Shively John; Judenhofer Martin S; Machulla Hans-Jurgen; Pichler Bernd J
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine (2009), 50 (4), 606-11 ISSN:0161-5505.
    UNLABELLED: Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, is highly expressed by virtually all prostate cancers and is currently the focus of several diagnostic and therapeutic strategies. We have previously reported on the generation of several monoclonal antibodies (mAb) and antibody fragments that recognize and bind with high affinity to the extracellular domain of cell-adherent PSMA. This article reports the in vivo behavior and tumor uptake of the radiolabeled anti-PSMA mAb 3/A12 and its potential as a tracer for PET. METHODS: The mAb 3/A12 was conjugated with the chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) and radiolabeled with (64)Cu. Severe combined immunodeficient mice bearing PSMA-positive C4-2 prostate carcinoma xenografts were used for small-animal PET imaging. Mice with PSMA-negative DU 145 tumors served as controls. For PET studies, each animal received 20-30 microg of radiolabeled mAb corresponding to an activity of 7.6-11.5 MBq. Imaging was performed 3, 24, and 48 h after injection. After the last scan, the mice were sacrificed and tracer in vivo biodistribution was measured by gamma-counting. RESULTS: Binding of the mAb 3/A12 on PSMA-expressing C4-2 cells was only minimally influenced by DOTA conjugation. The labeling efficiency using (64)Cu and DOTA-3/A12 was 95.3% +/- 0.3%. The specific activity after (64)Cu labeling was between 327 and 567 MBq/mg. After tracer injection, static small-animal PET images of mice with PSMA-positive tumors revealed a tumor-to-background ratio of 3.3 +/- 1.3 at 3 h, 7.8 +/- 1.4 at 24 h, and 9.6 +/- 2.7 at 48 h. In contrast, no significant tracer uptake occurred in the PSMA-negative DU 145 tumors. These results were confirmed by direct counting of tissues after the final imaging. CONCLUSION: Because of the high and specific uptake of (64)Cu-labeled mAb 3/A12 in PSMA-positive tumors, this ligand represents an excellent candidate for prostate cancer imaging and potentially for radioimmunotherapy.
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  67. 67
    Alt, K.; Wiehr, S.; Ehrlichmann, W.; Reischl, G.; Wolf, P.; Pichler, B. J.; Elsasser-Beile, U.; Buhler, P. High-resolution animal PET imaging of prostate cancer xenografts with three different 64Cu-labeled antibodies against native cell-adherent PSMA Prostate 2010, 70, 1413– 1421
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    There is no corresponding record for this reference.
  68. 68
    Fischer, G.; Seibold, U.; Schirrmacher, R.; Wangler, B.; Wangler, C. (89)Zr, a radiometal nuclide with high potential for molecular imaging with PET: chemistry, applications and remaining challenges Molecules 2013, 18, 6469– 6490
    Google Scholar
    There is no corresponding record for this reference.
  69. 69
    Cheng, Y.; Prusoff, W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50% inhibition (I50) of an enzymatic reaction Biochem. Pharmacol. 1973, 22, 3099– 3108
    Google Scholar
    69
    Relation between the inhibition constant K1) and the concentration of inhibitor which causes fifty per cent inhibition (I50) of an enzymic reaction
    Cheng, Yung-Chi; Prusoff, William H.
    Biochemical Pharmacology (1973), 22 (23), 3099-108CODEN: BCPCA6; ISSN:0006-2952.
    The Ki and I50 values are equal where the kinetics are non- or uncompetitive, but not where they are competitive. The relation between the 2 values was analyzed for non- and uncompetitive bi- and monosubstrate reactions and for competitive bisubstrate reactions.
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  9. Ananda Kumar Kanduluru, Madduri Srinivasarao, and Philip S. Low . Design, Synthesis, and Evaluation of a Neurokinin-1 Receptor-Targeted Near-IR Dye for Fluorescence-Guided Surgery of Neuroendocrine Cancers. Bioconjugate Chemistry 2016, 27 (9) , 2157-2165. https://doi.org/10.1021/acs.bioconjchem.6b00374
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  18. Inki Lee, Min Hwan Kim, Kyongkyu Lee, Keumrok Oh, Hyunwoo Lim, Jae Hun Ahn, Yong Jin Lee, Gi Jeong Cheon, Dae Yoon Chi, Sang Moo Lim. Comparison of the Effects of DOTA and NOTA Chelators on 64Cu-Cudotadipep and 64Cu-Cunotadipep for Prostate Cancer. Diagnostics 2023, 13 (16) , 2649. https://doi.org/10.3390/diagnostics13162649
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  23. Sarah D. Busslinger, Viviane J. Tschan, Olivia K. Richard, Zeynep Talip, Roger Schibli, Cristina Müller. [225Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [225Ac]Ac-PSMA-617. Cancers 2022, 14 (22) , 5651. https://doi.org/10.3390/cancers14225651
  24. Beshara Sheehan, Christina Guo, Antje Neeb, Alec Paschalis, Shahneen Sandhu, Johann S. de Bono. Prostate-specific Membrane Antigen Biology in Lethal Prostate Cancer and its Therapeutic Implications. European Urology Focus 2022, 8 (5) , 1157-1168. https://doi.org/10.1016/j.euf.2021.06.006
  25. Thomas M. Jeitner, John W. Babich, James M. Kelly. Advances in PSMA theranostics. Translational Oncology 2022, 22 , 101450. https://doi.org/10.1016/j.tranon.2022.101450
  26. Chul-Hee Lee, Ilhan Lim, Sang-Keun Woo, Kwang Il Kim, Kyo Chul Lee, Kanghyon Song, Chang Woon Choi, Sang Moo Lim. The Feasibility of 64 Cu-PSMA I&T PET for Prostate Cancer. Cancer Biotherapy and Radiopharmaceuticals 2022, 37 (6) , 417-423. https://doi.org/10.1089/cbr.2020.4189
  27. Marie-Christine Milot, Ophélie Bélissant Benesty, Véronique Dumulon-Perreault, Samia Ait-Mohand, Patrick O. Richard, Étienne Rousseau, Brigitte Guérin. 64Cu-DOTHA2-PSMA, a Novel PSMA PET Radiotracer for Prostate Cancer with a Long Imaging Time Window. Pharmaceuticals 2022, 15 (8) , 996. https://doi.org/10.3390/ph15080996
  28. David G. Calatayud, Sotia Neophytou, Eleni Nicodemou, S. Giuseppe Giuffrida, Haobo Ge, Sofia I. Pascu. Nano-Theranostics for the Sensing, Imaging and Therapy of Prostate Cancers. Frontiers in Chemistry 2022, 10 https://doi.org/10.3389/fchem.2022.830133
  29. Truc T. Huynh, Sreeja Sreekumar, Cedric Mpoy, Buck E. Rogers. A comparison of 64Cu-labeled bi-terminally PEGylated A20FMDV2 peptides targeting integrin ανβ6. Oncotarget 2022, 13 (1) , 360-372. https://doi.org/10.18632/oncotarget.28197
  30. B. Liu, R. Han, C. Yuan, H. Sun, Z. Chen, G. Tian, F. Shi, X. Zhang, P. Luo, H. Jia. Excitation functions of proton induced reactions on titanium and copper. Applied Radiation and Isotopes 2021, 173 , 109713. https://doi.org/10.1016/j.apradiso.2021.109713
  31. Andrew Siow, Renata Kowalczyk, Margaret A. Brimble, Paul W.R. Harris. Evolution of Peptide-Based Prostate-Specific Membrane Antigen (PSMA) Inhibitors: An Approach to Novel Prostate Cancer Therapeutics. Current Medicinal Chemistry 2021, 28 (19) , 3713-3752. https://doi.org/10.2174/0929867327666201006153847
  32. Lachlan E. McInnes, Carleen Cullinane, Peter D. Roselt, Susan Jackson, Benjamin J. Blyth, Ellen M. van Dam, Nicholas A. Zia, Matthew J. Harris, Rodney J. Hicks, Paul S. Donnelly. Therapeutic Efficacy of a Bivalent Inhibitor of Prostate-Specific Membrane Antigen Labeled with 67 Cu. Journal of Nuclear Medicine 2021, 62 (6) , 829-832. https://doi.org/10.2967/jnumed.120.251579
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  34. Mária Bodnár Mikulová, Peter Mikuš. Advances in Development of Radiometal Labeled Amino Acid-Based Compounds for Cancer Imaging and Diagnostics. Pharmaceuticals 2021, 14 (2) , 167. https://doi.org/10.3390/ph14020167
  35. Dhanusha Sabanathan, Maria E. Lund, Douglas H. Campbell, Bradley J. Walsh, Howard Gurney. Radioimmunotherapy for solid tumors: spotlight on Glypican-1 as a radioimmunotherapy target. Therapeutic Advances in Medical Oncology 2021, 13 , 175883592110229. https://doi.org/10.1177/17588359211022918
  36. Nikhil Mayor, Niranjan J. Sathianathen, James Buteau, Samantha Koschel, Marta Antón Juanilla, Jada Kapoor, Arun Azad, Michael S. Hofman, Declan G. Murphy. Prostate‐specific membrane antigen theranostics in advanced prostate cancer: an evolving option. BJU International 2020, 126 (5) , 525-535. https://doi.org/10.1111/bju.15143
  37. Nicholas P. van der Meulen, Roger Hasler, Zeynep Talip, Pascal V. Grundler, Chiara Favaretto, Christoph A. Umbricht, Cristina Müller, Gaia Dellepiane, Tommaso S. Carzaniga, Saverio Braccini. Developments toward the Implementation of 44Sc Production at a Medical Cyclotron. Molecules 2020, 25 (20) , 4706. https://doi.org/10.3390/molecules25204706
  38. Lukas Greifenstein, Denise Späth, Jean Phillip Sinnes, Tilmann Grus, Frank Rösch. Mild and efficient 64 Cu labeling of perhydro-1, 4-diazepine derivatives for potential use with large peptides, proteins and antibodies. Radiochimica Acta 2020, 108 (7) , 555-563. https://doi.org/10.1515/ract-2019-3167
  39. Mathieu L. Lepage, Hsiou‐Ting Kuo, Áron Roxin, Sungjoon Huh, Zhengxing Zhang, Rajaguru Kandasamy, Helen Merkens, Joel O. Kumlin, Alan Limoges, Stefan K. Zeisler, Kuo‐Shyan Lin, François Bénard, David M. Perrin. Toward 18 F‐Labeled Theranostics: A Single Agent that Can Be Labeled with 18 F, 64 Cu, or 177 Lu. ChemBioChem 2020, 21 (7) , 943-947. https://doi.org/10.1002/cbic.201900632
  40. Thomas L. Andersen, Christina Baun, Birgitte B. Olsen, Johan H. Dam, Helge Thisgaard. Improving Contrast and Detectability: Imaging with [ 55 Co]Co-DOTATATE in Comparison with [ 64 Cu]Cu-DOTATATE and [ 68 Ga]Ga-DOTATATE. Journal of Nuclear Medicine 2020, 61 (2) , 228-233. https://doi.org/10.2967/jnumed.119.233015
  41. Brett A. Vaughn, Shin Hye Ahn, Eduardo Aluicio-Sarduy, Justin Devaraj, Aeli P. Olson, Jonathan Engle, Eszter Boros. Chelation with a twist: a bifunctional chelator to enable room temperature radiolabeling and targeted PET imaging with scandium-44. Chemical Science 2020, 11 (2) , 333-342. https://doi.org/10.1039/C9SC04655K
  42. José Carlos dos Santos, Barbro Beijer, Ulrike Bauder-Wüst, Martin Schäfer, Karin Leotta, Matthias Eder, Martina Benešová, Christian Kleist, Frederik Giesel, Clemens Kratochwil, Klaus Kopka, Uwe Haberkorn, Walter Mier. Development of Novel PSMA Ligands for Imaging and Therapy with Copper Isotopes. Journal of Nuclear Medicine 2020, 61 (1) , 70-79. https://doi.org/10.2967/jnumed.119.229054
  43. Nadeem Ahmed Lodhi, Ji Yong Park, Kyuwan Kim, Mi Kyung Hong, Young Joo Kim, Yun-Sang Lee, Gi Jeong Cheon, Keon Wook Kang, Jae Min Jeong. Synthesis and Evaluation of 99mTc-Tricabonyl Labeled Isonitrile Conjugates for Prostate-Specific Membrane Antigen (PSMA) Image. Inorganics 2020, 8 (1) , 5. https://doi.org/10.3390/inorganics8010005
  44. Christoph A. Umbricht, Ulli Köster, Peter Bernhardt, Nadezda Gracheva, Karl Johnston, Roger Schibli, Nicholas P. van der Meulen, Cristina Müller. Alpha-PET for Prostate Cancer: Preclinical investigation using 149Tb-PSMA-617. Scientific Reports 2019, 9 (1) https://doi.org/10.1038/s41598-019-54150-w
  45. Sangeeta Ray Banerjee, Vivek Kumar, Ala Lisok, Jian Chen, Il Minn, Mary Brummet, Srikanth Boinapally, Michael Cole, Ethel Ngen, Bryan Wharram, Cory Brayton, Robert F. Hobbs, Martin G. Pomper. 177Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy. European Journal of Nuclear Medicine and Molecular Imaging 2019, 46 (12) , 2545-2557. https://doi.org/10.1007/s00259-019-04434-0
  46. Xiaoxia Zhu, Xiaye Miao, Xinyue Qin, Xiaohong Zhu. Design of immunogens: The effect of bifunctional chelator on immunological response to chelated copper. Journal of Pharmaceutical and Biomedical Analysis 2019, 174 , 263-269. https://doi.org/10.1016/j.jpba.2019.06.001
  47. Niels J. Rupp, Christoph A. Umbricht, Daniele A. Pizzuto, Daniela Lenggenhager, Antonia Töpfer, Julian Müller, Urs J. Muehlematter, Daniela A. Ferraro, Michael Messerli, Grégoire B. Morand, Gerhard F. Huber, Daniel Eberli, Roger Schibli, Cristina Müller, Irene A. Burger. First Clinicopathologic Evidence of a Non–PSMA-Related Uptake Mechanism for 68 Ga-PSMA-11 in Salivary Glands. Journal of Nuclear Medicine 2019, 60 (9) , 1270-1276. https://doi.org/10.2967/jnumed.118.222307
  48. Sagnik Sengupta, Mena Asha Krishnan, Sudeshna Chattopadhyay, Venkatesh Chelvam. Comparison of prostate‐specific membrane antigen ligands in clinical translation research for diagnosis of prostate cancer. Cancer Reports 2019, 2 (4) https://doi.org/10.1002/cnr2.1169
  49. Clemens Kratochwil, Uwe Haberkorn, Frederik L. Giesel. Radionuclide Therapy of Metastatic Prostate Cancer. Seminars in Nuclear Medicine 2019, 49 (4) , 313-325. https://doi.org/10.1053/j.semnuclmed.2019.02.003
  50. Hans-Jürgen Wester, Margret Schottelius. PSMA-Targeted Radiopharmaceuticals for Imaging and Therapy. Seminars in Nuclear Medicine 2019, 49 (4) , 302-312. https://doi.org/10.1053/j.semnuclmed.2019.02.008
  51. Sebastian Hoberück, Gerd Wunderlich, Enrico Michler, Tobias Hölscher, Martin Walther, Danilo Seppelt, Ivan Platzek, Klaus Zöphel, Jörg Kotzerke. Dual‐time‐point 64 Cu‐PSMA ‐617‐ PET/CT in patients suffering from prostate cancer. Journal of Labelled Compounds and Radiopharmaceuticals 2019, 62 (8) , 523-532. https://doi.org/10.1002/jlcr.3745
  52. Nadine Leygue, Morgane Enel, Abdel Diallo, Béatrice Mestre‐Voegtlé, Chantal Galaup, Claude Picard. Efficient Synthesis of a Family of Bifunctional Chelators Based on the PCTA[12] Macrocycle Suitable for Bioconjugation. European Journal of Organic Chemistry 2019, 2019 (18) , 2899-2913. https://doi.org/10.1002/ejoc.201900280
  53. Till Wüstemann, Uwe Haberkorn, John Babich, Walter Mier. Targeting prostate cancer: Prostate‐specific membrane antigen based diagnosis and therapy. Medicinal Research Reviews 2019, 39 (1) , 40-69. https://doi.org/10.1002/med.21508
  54. Yeye Zhou, Jihui Li, Xin Xu, Man Zhao, Bin Zhang, Shengming Deng, Yiwei Wu. 64 Cu-based Radiopharmaceuticals in Molecular Imaging. Technology in Cancer Research & Treatment 2019, 18 , 153303381983075. https://doi.org/10.1177/1533033819830758
  55. Amandine Conte‐Daban, Maryline Beyler, Raphaël Tripier, Christelle Hureau. Kinetics Are Crucial When Targeting Copper Ions to Fight Alzheimer's Disease: An Illustration with Azamacrocyclic Ligands. Chemistry – A European Journal 2018, 24 (33) , 8447-8452. https://doi.org/10.1002/chem.201801520
  56. Tilman Läppchen, Yvonne Kiefer, Jason P. Holland, Mark D. Bartholomä. In vitro and in vivo evaluation of the bifunctional chelator NODIA-Me in combination with a prostate-specific membrane antigen targeting vector. Nuclear Medicine and Biology 2018, 60 , 45-54. https://doi.org/10.1016/j.nucmedbio.2018.03.002
  57. Zhihao Zha, Karl Ploessl, Seok Rye Choi, Zehui Wu, Lin Zhu, Hank F. Kung. Synthesis and evaluation of a novel urea-based 68 Ga-complex for imaging PSMA binding in tumor. Nuclear Medicine and Biology 2018, 59 , 36-47. https://doi.org/10.1016/j.nucmedbio.2017.12.007
  58. Shankar Vallabhajosula, Berna D. Polack, John W. Babich. Molecular Imaging of Prostate Cancer: Radiopharmaceuticals for Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT). 2018, 475-501. https://doi.org/10.1007/978-3-319-64096-9_27
  59. Christoph A. Umbricht, Martina Benešová, Raffaella M. Schmid, Andreas Türler, Roger Schibli, Nicholas P. van der Meulen, Cristina Müller. 44Sc-PSMA-617 for radiotheragnostics in tandem with 177Lu-PSMA-617—preclinical investigations in comparison with 68Ga-PSMA-11 and 68Ga-PSMA-617. EJNMMI Research 2017, 7 (1) https://doi.org/10.1186/s13550-017-0257-4
  60. Sara Sheikhbahaei, Ali Afshar-Oromieh, Matthias Eiber, Lilja B. Solnes, Mehrbod S. Javadi, Ashley E. Ross, Kenneth J. Pienta, Mohamad E. Allaf, Uwe Haberkorn, Martin G. Pomper, Michael A. Gorin, Steven P. Rowe. Pearls and pitfalls in clinical interpretation of prostate-specific membrane antigen (PSMA)-targeted PET imaging. European Journal of Nuclear Medicine and Molecular Imaging 2017, 44 (12) , 2117-2136. https://doi.org/10.1007/s00259-017-3780-7
  61. Lingzhou Zhao, Xiangyang Shi, Jinhua Zhao. Dendrimer-based contrast agents for PET imaging. Drug Delivery 2017, 24 (2) , 81-93. https://doi.org/10.1080/10717544.2017.1399299
  62. Tadahiro Kin, Takaya Kawagoe, Shouhei Araki, Yukinobu Watanabe. Production of high-purity medical radio isotope 64 Cu with accelerator-based neutrons generated with 9 and 12 MeV deuterons. Journal of Nuclear Science and Technology 2017, 54 (10) , 1123-1130. https://doi.org/10.1080/00223131.2017.1344585
  63. Aimen Zlitni, Melissa Yin, Nancy Janzen, Samit Chatterjee, Ala Lisok, Kathleen L. Gabrielson, Sridhar Nimmagadda, Martin G. Pomper, F. Stuart Foster, John F. Valliant, . Development of prostate specific membrane antigen targeted ultrasound microbubbles using bioorthogonal chemistry. PLOS ONE 2017, 12 (5) , e0176958. https://doi.org/10.1371/journal.pone.0176958
  64. Xiaoping Xu, Jianping Zhang, Silong Hu, Simin He, Xiao Bao, Guang Ma, Jianmin Luo, Jingyi Cheng, Yingjian Zhang. 99m Tc-labeling and evaluation of a HYNIC modified small-molecular inhibitor of prostate-specific membrane antigen. Nuclear Medicine and Biology 2017, 48 , 69-75. https://doi.org/10.1016/j.nucmedbio.2017.01.010
  65. Aviral Singh, Harshad R. Kulkarni, Richard P. Baum. Imaging of Prostate Cancer Using 64 Cu-Labeled Prostate-Specific Membrane Antigen Ligand. PET Clinics 2017, 12 (2) , 193-203. https://doi.org/10.1016/j.cpet.2016.12.001
  66. Eleni Gourni, Gjermund Henriksen. Metal-Based PSMA Radioligands. Molecules 2017, 22 (4) , 523. https://doi.org/10.3390/molecules22040523
  67. Uwe Haberkorn, Matthias Eder, Klaus Kopka, John W. Babich, Michael Eisenhut. Role of Radiolabelled Small Molecules Binding to PSMA in Diagnosis and Therapy of Prostate Cancer. 2017, 51-58. https://doi.org/10.1007/978-3-319-57624-4_6
  68. Gerhard Glatting, Carmen Wängler, Björn Wängler. Physikalisch-technische Grundlagen und Tracerentwicklung in der Positronenemissionstomografie. 2017, 19-56. https://doi.org/10.1007/978-3-662-50468-0_2
  69. Mariane Le Fur, Maryline Beyler, Enikő Molnár, Olivier Fougère, David Esteban-Gómez, Gyula Tircsó, Carlos Platas-Iglesias, Nicolas Lepareur, Olivier Rousseaux, Raphaël Tripier. The role of the capping bond effect on pyclen nat Y 3+ / 90 Y 3+ chelates: full control of the regiospecific N-functionalization makes the difference. Chemical Communications 2017, 53 (69) , 9534-9537. https://doi.org/10.1039/C7CC05088G
  70. Eleni Gourni, Luigi Del Pozzo, Mark Bartholomä, Yvonne Kiefer, Philipp T. Meyer, Helmut R. Maecke, Jason P. Holland. Radiochemistry and Preclinical PET Imaging of 68 Ga-Desferrioxamine Radiotracers Targeting Prostate-Specific Membrane Antigen. Molecular Imaging 2017, 16 , 153601211773701. https://doi.org/10.1177/1536012117737010
  71. Andreas Poschenrieder, Margret Schottelius, Markus Schwaiger, Horst Kessler, Hans-Jürgen Wester. The influence of different metal-chelate conjugates of pentixafor on the CXCR4 affinity. EJNMMI Research 2016, 6 (1) https://doi.org/10.1186/s13550-016-0193-8
  72. James C Evans, Meenakshi Malhotra, John F Cryan, Caitriona M O'Driscoll. The therapeutic and diagnostic potential of the prostate specific membrane antigen/glutamate carboxypeptidase II (PSMA/GCPII) in cancer and neurological disease. British Journal of Pharmacology 2016, 173 (21) , 3041-3079. https://doi.org/10.1111/bph.13576
  73. Ali Afshar-Oromieh, John W. Babich, Clemens Kratochwil, Frederik L. Giesel, Michael Eisenhut, Klaus Kopka, Uwe Haberkorn. The Rise of PSMA Ligands for Diagnosis and Therapy of Prostate Cancer. Journal of Nuclear Medicine 2016, 57 (Supplement 3) , 79S-89S. https://doi.org/10.2967/jnumed.115.170720
  74. Eric Wehrenberg-Klee, N. Selcan Turker, Pedram Heidari, Benjamin Larimer, Dejan Juric, José Baselga, Maurizio Scaltriti, Umar Mahmood. Differential Receptor Tyrosine Kinase PET Imaging for Therapeutic Guidance. Journal of Nuclear Medicine 2016, 57 (9) , 1413-1419. https://doi.org/10.2967/jnumed.115.169417
  75. Il Minn, Soo Min Koo, Hye Soo Lee, Mary Brummet, Steven P. Rowe, Michael A. Gorin, Polina Sysa-Shah, William D. Lewis, Hye-Hyun Ahn, Yuchuan Wang, Sangeeta Ray Banerjee, Ronnie C. Mease, Sridhar Nimmagadda, Mohamad E. Allaf, Martin G. Pomper, Xing Yang. [64Cu]XYIMSR-06: A dual-motif CAIX ligand for PET imaging of clear cell renal cell carcinoma. Oncotarget 2016, 7 (35) , 56471-56479. https://doi.org/10.18632/oncotarget.10602
  76. Ali Afshar-Oromieh, Henrik Hetzheim, Wolfgang Kübler, Clemens Kratochwil, Frederik L. Giesel, Thomas A. Hope, Matthias Eder, Michael Eisenhut, Klaus Kopka, Uwe Haberkorn. Radiation dosimetry of 68Ga-PSMA-11 (HBED-CC) and preliminary evaluation of optimal imaging timing. European Journal of Nuclear Medicine and Molecular Imaging 2016, 43 (9) , 1611-1620. https://doi.org/10.1007/s00259-016-3419-0
  77. Jessie R. Nedrow, Joseph D. Latoche, Kathryn E. Day, Jalpa Modi, Tanushree Ganguly, Dexing Zeng, Brenda F. Kurland, Clifford E. Berkman, Carolyn J. Anderson. Targeting PSMA with a Cu-64 Labeled Phosphoramidate Inhibitor for PET/CT Imaging of Variant PSMA-Expressing Xenografts in Mouse Models of Prostate Cancer. Molecular Imaging and Biology 2016, 18 (3) , 402-410. https://doi.org/10.1007/s11307-015-0908-7
  78. Drishty Satpati, Ajit Shinto, K. K. Kamaleshwaran, Surekha Sane, Sharmila Banerjee. Convenient Preparation of [68Ga]DKFZ-PSMA-11 Using a Robust Single-Vial Kit and Demonstration of Its Clinical Efficacy. Molecular Imaging and Biology 2016, 18 (3) , 420-427. https://doi.org/10.1007/s11307-016-0943-z
  79. Vikas Prasad, Ingo G. Steffen, Gerd Diederichs, Marcus R. Makowski, Peter Wust, Winfried Brenner. Biodistribution of [68Ga]PSMA-HBED-CC in Patients with Prostate Cancer: Characterization of Uptake in Normal Organs and Tumour Lesions. Molecular Imaging and Biology 2016, 18 (3) , 428-436. https://doi.org/10.1007/s11307-016-0945-x
  80. Zhihang Chen, Marie-France Penet, Balaji Krishnamachary, Sangeeta R. Banerjee, Martin G. Pomper, Zaver M. Bhujwalla. PSMA-specific theranostic nanoplex for combination of TRAIL gene and 5-FC prodrug therapy of prostate cancer. Biomaterials 2016, 80 , 57-67. https://doi.org/10.1016/j.biomaterials.2015.11.048
  81. Laura K. van Dijk, Cheng‐Bin Yim, Gerben M. Franssen, Johannes H. A. M. Kaanders, Johan Rajander, Olof Solin, Tove J. Grönroos, Otto C. Boerman, Johan Bussink. PET of EGFR with 64 Cu‐cetuximab‐F(ab′) 2 in mice with head and neck squamous cell carcinoma xenografts. Contrast Media & Molecular Imaging 2016, 11 (1) , 65-70. https://doi.org/10.1002/cmmi.1659
  82. Fan Pu, Mani Salarian, Shenghui Xue, Jingjuan Qiao, Jie Feng, Shanshan Tan, Anvi Patel, Xin Li, Kenza Mamouni, Khan Hekmatyar, Juan Zou, Daqing Wu, Jenny J. Yang. Prostate-specific membrane antigen targeted protein contrast agents for molecular imaging of prostate cancer by MRI. Nanoscale 2016, 8 (25) , 12668-12682. https://doi.org/10.1039/C5NR09071G
  83. Uwe Haberkorn, Matthias Eder, Klaus Kopka, John W. Babich, Michael Eisenhut. New Strategies in Prostate Cancer: Prostate-Specific Membrane Antigen (PSMA) Ligands for Diagnosis and Therapy. Clinical Cancer Research 2016, 22 (1) , 9-15. https://doi.org/10.1158/1078-0432.CCR-15-0820
  84. Eleni Gourni, Coline Canovas, Victor Goncalves, Franck Denat, Philipp T. Meyer, Helmut R. Maecke, . (R)-NODAGA-PSMA: A Versatile Precursor for Radiometal Labeling and Nuclear Imaging of PSMA-Positive Tumors. PLOS ONE 2015, 10 (12) , e0145755. https://doi.org/10.1371/journal.pone.0145755
  85. Shaik Mohammad Naushad, Parvathaneni Shree Divyya, M. Janaki Ramaiah, Balraj Alex Stanley, S. Prasanna Lakshmi, J. Vishnupriya, Vijay Kumar Kutala. Clinical utility of genetic variants of glutamate carboxypeptidase II in predicting breast cancer and prostate cancer risk. Cancer Genetics 2015, 208 (11) , 552-558. https://doi.org/10.1016/j.cancergen.2015.09.001
  86. Ali Afshar-Oromieh, Henrik Hetzheim, Clemens Kratochwil, Martina Benesova, Matthias Eder, Oliver C. Neels, Michael Eisenhut, Wolfgang Kübler, Tim Holland-Letz, Frederik L. Giesel, Walter Mier, Klaus Kopka, Uwe Haberkorn. The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET/CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions. Journal of Nuclear Medicine 2015, 56 (11) , 1697-1705. https://doi.org/10.2967/jnumed.115.161299
  87. Zhengtao Qin. Recent advances of injectable radiopharmaceuticals for nuclear imaging and therapy: a new era in nuclear medicine. Materials Technology 2015, 30 (sup8) , B250-B255. https://doi.org/10.1080/10667857.2015.1104829
  88. Punit Sharma, Rakesh Kumar, Abass Alavi. PET/Computed Tomography Using New Radiopharmaceuticals in Targeted Therapy. PET Clinics 2015, 10 (4) , 495-505. https://doi.org/10.1016/j.cpet.2015.05.007
  89. Shanna Litau, Uwe Seibold, Alicia Vall‐Sagarra, Gert Fricker, Björn Wängler, Carmen Wängler. Comparative Assessment of Complex Stabilities of Radiocopper Chelating Agents by a Combination of Complex Challenge and in vivo Experiments. ChemMedChem 2015, 10 (7) , 1200-1208. https://doi.org/10.1002/cmdc.201500132
  90. T. Maurer, H. Kübler, J.E. Gschwend, M. Eiber. Positronenemissionstomographie bei urologischen Tumorerkrankungen. Der Urologe 2015, 54 (7) , 983-991. https://doi.org/10.1007/s00120-015-3868-2
  91. Ewen Bodio, Mohammed Boujtita, Karine Julienne, Patricia Le Saec, Sébastien G. Gouin, Jonathan Hamon, Eric Renault, David Deniaud. Synthesis and Characterization of a Stable Copper(I) Complex for Radiopharmaceutical Applications. ChemPlusChem 2014, 79 (9) , 1284-1293. https://doi.org/10.1002/cplu.201402031
  92. Amanda K. Pearce, Barbara E. Rolfe, Pamela J. Russell, Brian W.-C. Tse, Andrew K. Whittaker, Adrian V. Fuchs, Kristofer J. Thurecht. Development of a polymer theranostic for prostate cancer. Polym. Chem. 2014, 5 (24) , 6932-6942. https://doi.org/10.1039/C4PY00999A
  93. Robin C. Cumming, Dag Erlend Olberg, Julie L. Sutcliffe. Rapid 18 F-radiolabeling of peptides from [ 18 F]fluoride using a single microfluidics device. RSC Adv. 2014, 4 (90) , 49529-49534. https://doi.org/10.1039/C4RA10520F
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  • Abstract

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    Figure 1

    Figure 1. Proposed structures of 64Cu-labeled inhibitors of PSMA.

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    Scheme 1

    Scheme 1. Synthesis of [64Cu]3–5
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    Scheme 2

    Scheme 2. Synthesis of [64Cu]6
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    Figure 2

    Figure 2. Whole body PET-CT imaging of PSMA+ PC3 PIP and PSMA – PC3 flu tumor-bearing mice with compounds [64Cu]3, [64Cu]4, [64Cu]5, [64Cu]6B, and [64Cu]7 at 2.5 h postinjection, respectively. Mice were injected with ∼11.1 MBq (∼300 μCi) of radiotracer IV. PIP = PSMA+ PC3 PIP (solid arrow); flu = PSMA– PC3 flu (unfilled arrow); K= kidney; B = bladder; L = left; R = right. All images are decay-corrected and adjusted to the same maximum value.

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    Figure 3

    Figure 3. Whole body PET-CT imaging of PC3 PIP and PC3 flu tumor bearing mice with [64Cu]3 at 20 min (left), 6 h (middle), 28 h (right). Abdominal radioactivity is primarily due to uptake within kidneys and bladder. PIP = PC3 PSMA+ PIP (solid arrow); flu = PC3 PSMA– flu (unfilled arrow); K= kidney; L = left; R = right, B = bladder. All images are decay-corrected and adjusted to the same maximum value.

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    Figure 4

    Figure 4. Whole body PET-CT imaging of PC3 PIP and PC3 flu tumor bearing mice with [64Cu]6A (top row) and [64Cu]6B (bottom row) at 20 min, 2.5 h, 12 and 22 h postinjection. Abdominal radioactivity is primarily due to uptake within kidneys and bladder. PIP = PC3 PSMA+ PIP (solid arrow); flu = PC3 PSMA− flu (unfilled arrow); K= kidney; L = left; R = right, B = bladder. All images are decay-corrected and adjusted to the same maximum value.

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  • References

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    This article references 69 other publications.

    1. 1
      Ghosh, A.; Heston, W. D. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer J. Cell Biochem. 2004, 91, 528– 539
      Google Scholar
      1
      Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer
      Ghosh, Arundhati; Heston, Warren D. W.
      Journal of Cellular Biochemistry (2004), 91 (3), 528-539CODEN: JCEBD5; ISSN:0730-2312. (Wiley-Liss, Inc.)
      A review. Prostate specific membrane antigen (PSMA), is a unique membrane bound glycoprotein, which is overexpressed manifold on prostate cancer as well as neovasculature of most of the solid tumors, but not in the vasculature of the normal tissues. This unique expression of PSMA makes it an important marker as well as a large extracellular target of imaging agents. PSMA can serve as target for delivery of therapeutic agents such as cytotoxins or radionuclides. PSMA has two unique enzymic functions, folate hydrolase and NAALADase and found to be recycled like other membrane bound receptors through clathrin coated pits. The internalization property of PSMA leads one to consider the potential existence of a natural ligand for PSMA. In this review we have discussed the regulation of PSMA expression within the cells, and significance of its expression in prostate cancer and metastasis.
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    2. 2
      Rajasekaran, A. K.; Anilkumar, G.; Christiansen, J. J. Is prostate-specific membrane antigen a multifunctional protein? Am. J. Physiol., Cell Physiol. 2005, 288, C975– C981
      Google Scholar
      There is no corresponding record for this reference.
    3. 3
      Chang, S. S.; Reuter, V. E.; Heston, W. D.; Gaudin, P. B. Comparison of anti-prostate-specific membrane antigen antibodies and other immunomarkers in metastatic prostate carcinoma Urology 2001, 57, 1179– 1183
      Google Scholar
      3
      Comparison of anti-prostate-specific membrane antigen antibodies and other immunomarkers in metastatic prostate carcinoma
      Chang S S; Reuter V E; Heston W D; Gaudin P B
      Urology (2001), 57 (6), 1179-83 ISSN:.
      OBJECTIVES: To compare the immunohistochemical properties of the 7E11 anti-prostate-specific membrane antigen (anti-PSMA) monoclonal antibody (mAb) with the recently developed anti-PSMA mAb, PM2J004.5, and with other common immunomarkers in metastatic prostate cancer. PSMA is a type II integral membrane glycoprotein highly expressed in prostate cancer cells. The mAb 7E11 is currently used in the radioisotopic evaluation of prostate cancer, and its immunohistochemical properties have been examined in primary prostate cancer specimens. METHODS: We examined 23 formalin-fixed, paraffin-embedded, metastatic prostate carcinoma specimens from various anatomic sites, including bone, lymph node, liver, lung, and soft tissue. Using the biotin-streptavidin method, we performed immunohistochemical reactions with the anti-PSMA mAbs 7E11 and PM2J004.5 and with antibodies to prostate-specific antigen and prostatic acid phosphatase. The immunoreactions were scored by pathologists unaware of the clinical and pathologic data according to a staining intensity scale and the percentage of cells stained. RESULTS: All four mAbs consistently stained the metastatic prostate cancer specimens. In 2 (8.7%) of 23 cases, however, the prostate-specific antigen immunoreaction was negative but the anti-PSMA mAbs had positive staining. Although 7E11 and PM2J004.5 had a similar staining intensity and percentage of cells stained for most specimens, in 3 (13%) of 23 specimens, 7E11 had less intense staining. None of the specimens were negative for all four antibodies. CONCLUSIONS: Anti-PSMA mAbs consistently immunoreacted with metastatic prostate cancer specimens and were positive in instances when prostate-specific antigen staining was negative. The anti-PSMA mAbs demonstrated similar staining patterns; however, in select cases, the PM2J004.5 mAb did show more intense staining. The anti-PSMA mAbs 7E11 and PM2J004.5 are useful in the pathologic evaluation of paraffin-embedded metastatic prostate cancer specimens.
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    4. 4
      Wright, G. L., Jr.; Grob, B. M.; Haley, C.; Grossman, K.; Newhall, K.; Petrylak, D.; Troyer, J.; Konchuba, A.; Schellhammer, P. F.; Moriarty, R. Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy Urology 1996, 48, 326– 334
      Google Scholar
      4
      Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy
      Wright G L Jr; Grob B M; Haley C; Grossman K; Newhall K; Petrylak D; Troyer J; Konchuba A; Schellhammer P F; Moriarty R
      Urology (1996), 48 (2), 326-34 ISSN:0090-4295.
      OBJECTIVES: To determine the expression of prostate-specific membrane antigen (PSMA) before and after androgen-deprivation therapy and to compare PSMA expression with prostate-specific antigen (PSA) expression. METHODS: We studied specimens from 20 patients with prostate cancer undergoing medical or surgical castration or combination androgen-deprivation therapy in whom matched pretreatment and post-treatment tissue specimens were available and 16 patients in whom only a post-treatment specimen was available. The expression of PSMA and PSA in the tissue specimens was determined by immunoperoxidase staining. The extent of staining was calculated by multiplying the percent of antigen-positive tumor cells by the staining intensity to arrive at a stain index for each biomarker. An in vitro study assessed the concentration of PSMA and PSA in extracts of LNCaP cells cultured in the presence or absence of androgen as determined by immunoassays and Western blot analysis. RESULTS: PSMA reactivity was found to be increased in 55% (11 of 20) of post-treatment primary tissues and 100% (4 of 4) of post-treatment metastatic specimens. In contrast, PSA expression was found to be decreased in 70% (14 of 20) of post-treatment primary and 100% (4 of 4) of post-treatment metastatic specimens. Neither type of androgen-deprivation treatment nor tissue sensitivity to androgen deprivation appeared to influence degree of biomarker expression. PSMA was found to be downregulated and PSA upregulated when LNCaP cells were cultured in the presence of testosterone or dihydrotestosterone. CONCLUSIONS: The enhanced expression of PSMA in tissues and LNCaP cells after androgen deprivation suggests that PSMA is upregulated in the majority of prostate carcinomas after androgen treatment. The high expression in metastatic tissues strongly suggests that PSMA may be a clinically useful target for antibody-and genetic-directed therapy of prostate cancer that recurs after androgen deprivation. The mechanism whereby androgens suppress the expression of PSMA, and the association of PSMA with the development of hormone-independent prostate cancers, will require further study.
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    5. 5
      Evans, M. J.; Smith-Jones, P. M.; Wongvipat, J.; Navarro, V.; Kim, S.; Bander, N. H.; Larson, S. M.; Sawyers, C. L. Noninvasive measurement of androgen receptor signaling with a positron-emitting radiopharmaceutical that targets prostate-specific membrane antigen Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 9578– 9582
      Google Scholar
      There is no corresponding record for this reference.
    6. 6
      Perner, S.; Hofer, M. D.; Kim, R.; Shah, R. B.; Li, H.; Moller, P.; Hautmann, R. E.; Gschwend, J. E.; Kuefer, R.; Rubin, M. A. Prostate-specific membrane antigen expression as a predictor of prostate cancer progression Human Pathol. 2007, 38, 696– 701
      Google Scholar
      6
      Prostate-specific membrane antigen expression as a predictor of prostate cancer progression
      Perner, Sven; Hofer, Matthias D.; Kim, Robert; Shah, Rajal B.; Li, Haojie; Moeller, Peter; Hautmann, Richard E.; Gschwend, Juergen E.; Kuefer, Rainer; Rubin, Mark A.
      Human Pathology (2007), 38 (5), 696-701CODEN: HPCQA4; ISSN:0046-8177. (Elsevier Inc.)
      Distinguishing aggressive prostate cancer from indolent disease represents an important clin. challenge, because current therapy may lead to overtreatment of men with limited disease. The prostate-specific membrane antigen (PSMA) is a membrane-bound glycoprotein that is highly restricted to the prostate. Previously, studies analyzing the expression of PSMA have found an up-regulation in correlation with prostate cancer, particularly in advanced cancer. This assocn. is ideal for an application as a prognostic marker. In the current study, we characterized PSMA expression in a high-risk cohort and evaluated its potential use as predictive marker of prostate-specific antigen (PSA) recurrence. PSMA expression was analyzed by immunohistochem. using tissue microarrays composed of tumor samples from 450 patients. Protein intensity was recorded using a semiautomated quant. microscope system (ACIS II; Clarient Chromavision Medical Systems, San Juan Capistrano, CA). PSMA expression levels differed significantly (P < .001) between benign prostatic tissue, localized prostate cancer, and lymph node metastases. Dividing the cohort into high- and low-PSMA expressing cancers based on the median area of pos. staining, we found that high PSMA levels were assocd. with significant increase of PSA recurrence (P = .004). This was independent of clin. parameters such as lymph node tumor burden (lymph node d., >20%; P < .001), extraprostatic extension (P = .017), seminal vesicle invasion (P < .001), and high Gleason score (8-10, P = .006). In a multivariate model, PSMA expression and metastases to pelvic lymph nodes were significantly assocd. with time to PSA recurrence (HR, 1.4; 95% confidence interval, 1.1-2.8, P = .017; and hazard ratio, 5; 95% confidence interval, 2.6-9.7, P < .001, resp.). In summary, PSMA is independently assocd. with PSA recurrence in a high-risk cohort and thus might provide insight into the addnl. use of adjuvant therapy. Validation on other cohorts is required.
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    7. 7
      Sanna, V.; Pintus, G.; Roggio, A. M.; Punzoni, S.; Posadino, A. M.; Arca, A.; Marceddu, S.; Bandiera, P.; Uzzau, S.; Sechi, M. Targeted biocompatible nanoparticles for the delivery of (−)-epigallocatechin 3-gallate to prostate cancer cells J. Med. Chem. 2011, 54, 1321– 1332
      Google Scholar
      7
      Targeted Biocompatible Nanoparticles for the Delivery of (-)-Epigallocatechin 3-Gallate to Prostate Cancer Cells
      Sanna, Vanna; Pintus, Gianfranco; Roggio, Anna Maria; Punzoni, Stefania; Posadino, Anna Maria; Arca, Alessandro; Marceddu, Salvatore; Bandiera, Pasquale; Uzzau, Sergio; Sechi, Mario
      Journal of Medicinal Chemistry (2011), 54 (5), 1321-1332CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Mol. targeted cancer therapy mediated by nanoparticles (NPs) is a promising strategy to overcome the lack of specificity of conventional chemotherapeutic agents. In this context, the prostate-specific membrane antigen (PSMA) has demonstrated a powerful potential for the management of prostate cancer (PCa). Cancer chemoprevention by phytochems. is emerging as a suitable approach for the treatment of early carcinogenic processes. Since (-)-epigallocatechin 3-gallate (EGCG) has shown potent chemopreventive efficacy for PCa, we designed and developed novel targeted NPs in order to selectively deliver EGCG to cancer cells. Herein, to explore the recent concept of "nanochemoprevention", we present a study on EGCG-loaded NPs consisting of biocompatible polymers, functionalized with small mols. targeting PSMA, that exhibited a selective in vitro efficacy against PSMA-expressing PCa cells. This approach could be beneficial for high risk patients and would fulfill a significant therapeutic need, thus opening new perspectives for novel and effective treatment for PCa.
      >> More from SciFinder ®
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    8. 8
      DiPippo, V. A.; Magargal, W. W.; Moorji, S. M.; Murga, J. D.; Olson, W. C. Antiandrogen modulation of prostate-specific membrane antigen (PSMA): dynamics and synergy with PSMA-targeted therapy ASCO Meet. Abstr. 2013, 31, e16007
      Google Scholar
      There is no corresponding record for this reference.
    9. 9
      Petrylak, D. P.; Kantoff, P. W.; Mega, A. E.; Vogelzang, N. J.; Stephenson, J.; Fleming, M. T.; Stambler, N.; Petrini, M.; Blattman, S.; Israel, R. J. Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): a phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane ASCO Meet. Abstr. 2013, 31, 5018
      Google Scholar
      There is no corresponding record for this reference.
    10. 10
      Rotshteyn, Y.; Mercier, F.; Bruno, R.; Stambler, N.; Israel, R. J.; Wong, V. Correlation of PSMA ADC exposure with reduction in tumor growth rate determined using serial PSA measurements from a phase I clinical trial ASCO Meet. Abstr. 2013, 31, e16047
      Google Scholar
      There is no corresponding record for this reference.
    11. 11
      Hrkach, J.; Von Hoff, D.; Mukkaram Ali, M.; Andrianova, E.; Auer, J.; Campbell, T.; De Witt, D.; Figa, M.; Figueiredo, M.; Horhota, A.; Low, S.; McDonnell, K.; Peeke, E.; Retnarajan, B.; Sabnis, A.; Schnipper, E.; Song, J. J.; Song, Y. H.; Summa, J.; Tompsett, D.; Troiano, G.; Van Geen Hoven, T.; Wright, J.; LoRusso, P.; Kantoff, P. W.; Bander, N. H.; Sweeney, C.; Farokhzad, O. C.; Langer, R.; Zale, S. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile Sci. Transl. Med. 2012, 4, 128ra39
      Google Scholar
      There is no corresponding record for this reference.
    12. 12
      Hillier, S. M.; Maresca, K. P.; Femia, F. J.; Marquis, J. C.; Foss, C. A.; Nguyen, N.; Zimmerman, C. N.; Barrett, J. A.; Eckelman, W. C.; Pomper, M. G.; Joyal, J. L.; Babich, J. W. Preclinical evaluation of novel glutamate–urea–lysine analogues that target prostate-specific membrane antigen as molecular imaging pharmaceuticals for prostate cancer Cancer Res. 2009, 69, 6932– 6940
      Google Scholar
      12
      Preclinical Evaluation of Novel Glutamate-Urea-Lysine Analogues That Target Prostate-Specific Membrane Antigen as Molecular Imaging Pharmaceuticals for Prostate Cancer
      Hillier, Shawn M.; Maresca, Kevin P.; Femia, Frank J.; Marquis, John C.; Foss, Catherine A.; Nguyen, Nghi; Zimmerman, Craig N.; Barrett, John A.; Eckelman, William C.; Pomper, Martin G.; Joyal, John L.; Babich, John W.
      Cancer Research (2009), 69 (17), 6932-6940CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
      Prostate-specific membrane antigen (PSMA) is expressed in normal human prostate epithelium and is highly up-regulated in prostate cancer. We previously reported a series of novel small mol. inhibitors targeting PSMA. Two compds., MIP-1072, (S)-2-(3-((S)-1-carboxy-5-(4-iodobenzylamino)pentyl)ureido)pentanedioic acid, and MIP-1095, (S)-2-(3-((S)-1-carboxy-5-(3-(4-iodophenyl)ureido)pentyl)ureido)pentanedioic acid, were selected for further evaluation. MIP-1072 and MIP-1095 potently inhibited the glutamate carboxypeptidase activity of PSMA (Ki = 4.6 ± 1.6 nM and 0.24 ± 0.14 nM, resp.) and, when radiolabeled with 123I, exhibited high affinity for PSMA on human prostate cancer LNCaP cells (Kd = 3.8 ± 1.3 nM and 0.81 ± 0.39 nM, resp.). The assocn. of [123I]MIP-1072 and [123I]MIP-1095 with PSMA was specific; there was no binding to human prostate cancer PC3 cells, which lack PSMA, and binding was abolished by coincubation with a structurally unrelated NAALADase inhibitor, 2-(phosphonomethyl)pentanedioic acid (PMPA). [123I]MIP-1072 and [123I]MIP-1095 internalized into LNCaP cells at 37°C. Tissue distribution studies in mice showed 17.3 ± 6.3% (at 1 h) and 34.3 ± 12.7% (at 4 h) injected dose per g of LNCaP xenograft tissue, for [123I]MIP-1072 and [123I]MIP-1095, resp. [123I]MIP-1095 exhibited greater tumor uptake but slower washout from blood and nontarget tissues compared with [123I]MIP-1072. Specific binding to PSMA in vivo was shown by competition with PMPA in LNCaP xenografts, and the absence of uptake in PC3 xenografts. The uptake of [123I]MIP-1072 and [123I]MIP-1095 in tumor-bearing mice was corroborated by single-photon emission computed tomog./computed tomog. (SPECT/CT) imaging. PSMA-specific radiopharmaceuticals should provide a novel mol. targeting option for the detection and staging of prostate cancer.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtVOmtLzE&md5=f222208c3c3fbcaa376306c49c9ec80b
    13. 13
      Mease, R. C.; Foss, C. A.; Pomper, M. G. PET imaging in prostate cancer: focus on prostate-specific membrane antigen Curr. Top. Med. Chem. 2013, 13, 951– 962
      Google Scholar
      13
      PET imaging in prostate cancer: focus on prostate-specific membrane antigen
      Mease, Ronnie C.; Foss, Catherine A.; Pomper, Martin G.
      Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2013), 13 (8), 951-962CODEN: CTMCCL; ISSN:1568-0266. (Bentham Science Publishers Ltd.)
      A review. Prostate cancer (PCa) is the second leading cause of cancer-related death in American men. Positron emission tomog./computed tomog. (PET/CT) with emerging radiopharmaceuticals promises accurate staging of primary disease, restaging of recurrent disease, detection of metastatic lesions and, ultimately, for predicting the aggressiveness of disease. Prostate-specific membrane antigen (PSMA) is a well-characterized imaging biomarker of PCa. Because PSMA levels are directly related to androgen independence, metastasis and progression, PSMA could prove an important target for the development of new radiopharmaceuticals for PET. Preclin. data for new PSMA-based radiotracers are discussed and include new 89Zr- and 64Cu-labeled anti-PSMA antibodies and antibody fragments, 64Cu-labeled aptamers, and 11C-, 18F-, 68Ga-, 64Cu-, and 86Y-labeled low mol. wt. inhibitors of PSMA. Several of these agents, namely 68Ga- HBED-CC conjugate 15, 18F-DCFBC 8, and BAY1075553 are particularly promising, each having detected sites of PCa in initial clin. studies. These early clin. results suggest that PET/CT using PSMA-targeted agents, esp. with compds. of low mol. wt., will make valuable contributions to the management of PCa.
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    14. 14
      Cho, S. Y.; Gage, K. L.; Mease, R. C.; Senthamizhchelvan, S.; Holt, D. P.; Jeffrey-Kwanisai, A.; Endres, C. J.; Dannals, R. F.; Sgouros, G.; Lodge, M.; Eisenberger, M. A.; Rodriguez, R.; Carducci, M. A.; Rojas, C.; Slusher, B. S.; Kozikowski, A. P.; Pomper, M. G. Biodistribution, tumor detection, and radiation dosimetry of 18F–DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer J. Nucl. Med. 2012, 53, 1883– 1891
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    15. 15
      Afshar-Oromieh, A.; Malcher, A.; Eder, M.; Eisenhut, M.; Linhart, H. G.; Hadaschik, B. A.; Holland-Letz, T.; Giesel, F. L.; Kratochwil, C.; Haufe, S.; Haberkorn, U.; Zechmann, C. M. PET imaging with a [(68)Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions Eur. J. Nucl. Med. Mol. Imaging 2012, 40, 486– 495
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    16. 16
      Barrett, J. A.; Coleman, R. E.; Goldsmith, S. J.; Vallabhajosula, S.; Petry, N. A.; Cho, S.; Armor, T.; Stubbs, J. B.; Maresca, K. P.; Stabin, M. G.; Joyal, J. L.; Eckelman, W. C.; Babich, J. W. First-in-man evaluation of 2 high-affinity PSMA-avid small molecules for imaging prostate cancer J. Nucl. Med. 2013, 54, 380– 387
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      There is no corresponding record for this reference.
    17. 17
      Maresca, K. P.; Hillier, S. M.; Lu, G.; Marquis, J. C.; Zimmerman, C. N.; Eckelman, W. C.; Joyal, J. L.; Babich, J. W. Small molecule inhibitors of PSMA incorporating technetium-99m for imaging prostate cancer: effects of chelate design on pharmacokinetics Inorg. Chim. Acta 2012, 389, 168– 172
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      17
      Small molecule inhibitors of PSMA incorporating technetium-99m for imaging prostate cancer: Effects of chelate design on pharmacokinetics
      Maresca, Kevin P.; Hillier, Shawn M.; Lu, Genliang; Marquis, John C.; Zimmerman, Craig N.; Eckelman, William C.; Joyal, John L.; Babich, John W.
      Inorganica Chimica Acta (2012), 389 (), 168-175CODEN: ICHAA3; ISSN:0020-1693. (Elsevier B.V.)
      Single amino acid chelate (SAAC) systems for the complexation of the M(CO)3 moiety (M = Tc/Re) have been successfully incorporated into novel synthetic strategies for radiopharmaceuticals and evaluated in a variety of biol. applications. However, the lipophilicity of the first generation of 99mTc(CO)3 complexes has resulted in substantial hepatobiliary uptake when examd. either as lysine derivs. or integrated into biol. active small mols. and peptides. Here, we designed, synthesized, and evaluated novel polar functionalized imidazole derived SAAC systems (SAAC II) which have been chem. modified to promote overall 99mTc(CO)3L3 complex hydrophilicity with the intent of reducing non-target effects and enhancing renal clearance of prostate specific membrane antigen (PSMA) targeting small mols. The 99mTc-labeled compds. were prepd., purified, and evaluated for stability, lipophilicity, and tissue distribution in LNCaP xenograft mice. The Glu-urea-Lys-C11 analogs were prepd. with a variety of chelators to form (19R,23S)-1-(X)-2-((Y)methyl)-13,21-dioxo-2,14,20,22-tetraazapentacosane-19,23,25-tricarboxylic acid where X = Y = (methyl)pyridin-2-yl (6), X = Y = (methyl)-1H-imidazol-2-yl (7), X = (methyl)pyridin-2-yl, Y = carboxymethyl (8), X = Y = 1-(carboxymethyl)-1H-imidazol-2-yl (9), X = 1-(carboxymethyl)-1H-imidazol-2-yl, Y = carboxymethyl (10), and X = Y = 1-(1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl) (11). 99mTc labeling was achieved at ligand concns. as low as 10-6 M and the complexes were stable (>90%) for 24 h. These new SAAC II chelators were evaluated for their influence on binding of the Glu-urea-Lys-C11 analogs to PSMA-pos. LNCaP cells and compared to pyridine- and N-methylimidazole-contg. SAAC ligands. Tissue distribution of the 99mTc-complexes contg. the more polar chelators, 9 and 11, demonstrated decreased liver (<2% ID/g) and increased LNCaP tumor (>11% ID/g) accumulation at 1 h post-injection.
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    18. 18
      Nedrow-Byers, J. R.; Moore, A. L.; Ganguly, T.; Hopkins, M. R.; Fulton, M. D.; Benny, P. D.; Berkman, C. E. PSMA-targeted SPECT agents: Mode of binding effect on in vitro performance Prostate 2013, 73, 355– 362
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    19. 19
      Lu, G.; Maresca, K. P.; Hillier, S. M.; Zimmerman, C. N.; Eckelman, W. C.; Joyal, J. L.; Babich, J. W. Synthesis and SAR of 99mTc/Re-Labeled Small Molecule Prostate Specific Membrane Antigen Inhibitors with Novel Polar Chelates Biorg. Med. Chem. Lett. 2013, 23, 1557– 1563
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      19
      Synthesis and SAR of 99mTc/Re-labeled small molecule prostate specific membrane antigen inhibitors with novel polar chelates
      Lu, Genliang; Maresca, Kevin P.; Hillier, Shawn M.; Zimmerman, Craig N.; Eckelman, William C.; Joyal, John L.; Babich, John W.
      Bioorganic & Medicinal Chemistry Letters (2013), 23 (5), 1557-1563CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      Prostate specific membrane antigen (PSMA) is recognized as an attractive mol. target for the development of radiopharmaceuticals to image and potentially treat metastatic prostate cancer. A series of novel 99mTc/Re-tricarbonyl radiolabeled PSMA inhibitors were therefore synthesized by the attachment of glutamate-urea-lysine (Glu-urea-Lys) and glutamate-urea-glutamate (Glu-urea-Glu) pharmacophore to single amino acid chelate (SAAC) where the SAAC ligand was either bis(pyridin-2-ylmethyl)amino (DPA), bis((1-methyl-1H-imidazol-2-yl)methyl)amino (NMI), bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino (CIM) or bis((1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino (TIM). The in vitro binding affinity of the rhenium complexes was evaluated using PSMA-expressing human prostate cancer LNCaP cells. IC50 values ranged from 3.8 ± 2 to >2000 nM. A linker between the SAAC chelate and pharmacophore was required for high affinity binding. However, extending the length of the linker did not substantially improve binding. PSMA binding was also influenced by the nature of the SAAC chelate. One of the most potent compds., 23b (IC50 = 4.8 ± 2.7 nM), was radiolabeled with technetium tricarbonyl ({99mTc(CO)3}+) to afford the {99mTc(CO)3}+ complex in excellent yield and high purity. This effort led to the identification of a diverse series of promising high affinity {99mTc(CO)3}+ radiolabeled PSMA inhibitors.
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    20. 20
      Nedrow-Byers, J. R.; Jabbes, M.; Jewett, C.; Ganguly, T.; He, H.; Liu, T.; Benny, P.; Bryan, J. N.; Berkman, C. E. A phosphoramidate-based prostate-specific membrane antigen-targeted SPECT agent Prostate 2012, 72, 904– 912
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      There is no corresponding record for this reference.
    21. 21
      Banerjee, S. R.; Foss, C. A.; Castanares, M.; Mease, R. C.; Byun, Y.; Fox, J. J.; Hilton, J.; Lupold, S. E.; Kozikowski, A. P.; Pomper, M. G. Synthesis and evaluation of technetium-99m- and rhenium-labeled inhibitors of the prostate-specific membrane antigen (PSMA) J. Med. Chem. 2008, 51, 4504– 4517
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      21
      Synthesis and Evaluation of Technetium-99m- and Rhenium-Labeled Inhibitors of the Prostate-Specific Membrane Antigen (PSMA)
      Banerjee, Sangeeta R.; Foss, Catherine A.; Castanares, Mark; Mease, Ronnie C.; Byun, Youngjoo; Fox, James J.; Hilton, John; Lupold, Shawn E.; Kozikowski, Alan P.; Pomper, Martin G.
      Journal of Medicinal Chemistry (2008), 51 (15), 4504-4517CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for imaging and therapy of cancer. We prepd. seven 99mTc/Re-labeled compds. by attaching known Tc/Re chelating agents to an amino-functionalized PSMA inhibitor (lys-NHCONH-glu) with or without a variable length linker moiety. Ki values ranged from 0.17 to 199 nM. Ex vivo biodistribution and in vivo imaging demonstrated the degree of specific binding to engineered PSMA+ PC3 PIP tumors. PC3-PIP cells are derived from PC3 that have been transduced with the gene for PSMA. Despite demonstrating nearly the lowest PSMA inhibitory potency of this series, [99mTc(CO)3(L1)]+ (L1 = (2-pyridylmethyl)2N(CH2)4CH(CO2H)NHCO-(CH2)6CO-NH-lys-NHCONH-glu) showed the highest, most selective PIP tumor uptake, at 7.9 ± 4.0% injected dose per g of tissue at 30 min postinjection. Radioactivity cleared from nontarget tissues to produce a PIP to flu (PSMA-PC3) ratio of 44:1 at 120 min postinjection. PSMA can accommodate the steric requirements of 99mTc/Re complexes within PSMA inhibitors, the best results achieved with a linker moiety between the .vepsiln. amine of the urea lysine and the chelator.
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    22. 22
      Kularatne, S. A.; Zhou, Z.; Yang, J.; Post, C. B.; Low, P. S. Design, synthesis, and preclinical evaluation of prostate-specific membrane antigen targeted (99m)Tc-radioimaging agents Mol. Pharmaceutics 2009, 6, 790– 800
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      22
      Design, Synthesis, and Preclinical Evaluation of Prostate-Specific Membrane Antigen Targeted 99mTc-Radioimaging Agents
      Kularatne, Sumith A.; Zhou, Zhigang; Yang, Jun; Post, Carol B.; Low, Philip S.
      Molecular Pharmaceutics (2009), 6 (3), 790-800CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      The high mortality and financial burden assocd. with prostate cancer can be partly attributed to a lack of sensitive screening methods for detection and staging of the disease. Guided by in silico docking studies using the crystal structure of PSMA, we designed and synthesized a series of PSMA-targeted 99mTc-chelate complexes for imaging PSMA-expressing human prostate cancer cells (LNCaP cell line). Of the six targeted radioimaging agents synthesized, three were found to bind LNCaP cells with low nanomolar affinity. Moreover, the same three PSMA-targeted imaging agents were shown to localize primarily to LNCaP tumor xenografts in nu/nu mice, with an av. of 9.8 ± 2.4% injected dose/g tissue accumulating in the tumor and only 0.11% injected dose/g tissue retained in the muscle at 4 h postinjection. Collectively, these high affinity, PSMA-specific radioimaging agents demonstrate significant potential for use in localizing prostate cancer masses, monitoring response to therapy, detecting prostate cancer recurrence following surgery, and selecting patients for subsequent PSMA-targeted chemotherapy.
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    23. 23
      Zhang, Y.; DiFilipp, F.; Doke, A.; Huang, J.; Heston, W.; Huang, S. Preliminary micro-SPECT and biodistribution study of a novel Tc99m-labeled PSMA tracer derived from RBI1033 J. Nucl. Med. Meet. Abstr. 2012, 53 (Suppl 1) 1661
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    24. 24
      Schafer, M.; Bauder-Wust, U.; Leotta, K.; Zoller, F.; Mier, W.; Haberkorn, U.; Eisenhut, M.; Eder, M. A dimerized urea-based inhibitor of the prostate-specific membrane antigen for 68Ga-PET imaging of prostate cancer EJNMMI Res. 2012, 2, 23
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      A dimerized urea-based inhibitor of the prostate-specific membrane antigen for 68Ga-PET imaging of prostate cancer
      Schafer Martin; Bauder-Wust Ulrike; Leotta Karin; Zoller Frederic; Mier Walter; Haberkorn Uwe; Eisenhut Michael; Eder Matthias
      EJNMMI research (2012), 2 (1), 23 ISSN:.
      UNLABELLED: BACKGROUND: Alternative positron-emission tomography (PET) probes like labeled inhibitors of the prostate-specific membrane antigen (PSMA) are of emerging clinical impact as they show the ability to image small lesions of recurrent prostate cancer. Here, the dimerization of the pharmacophore Glu-ureido-Lys via the 68Ga chelator N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) was investigated to further improve the binding characteristics and pharmacokinetics. METHODS: The peptidomimetic structures were synthesized by solid-phase chemistry, and the resulting products were coupled with the respective 2,3,5,6-tetrafluorophenol esters of HBED-CC to form the monomeric reference and the dimeric Glu-ureido-Lys derivative. The binding properties were analyzed in competitive binding, internalization, and cell surface retention experiments. PET images and biodistribution data were obtained 1 h after injection in BALB/c nu/nu mice bearing LNCaP tumor xenografts. RESULTS: Cell binding data revealed significant better binding properties of the dimer (IC50 = 3.9 ± 1.8 nM; IC50 (monomer) = 12.1 ± 2.1 nM). The inhibition potency investigated by the enzyme-based NAALADase assay confirmed these results. Specific internalization in LNCaP cells was demonstrated for both, the monomer and dimer. As shown by efflux measurements, the dimeric compound was more effectively retained on the cell surface, resulting in advanced in vivo properties (T/BMonomer = 9.2; T/BDimer = 26.5). CONCLUSIONS: The dimeric [68Ga]7 is a promising imaging agent for PSMA-expressing tumors as it shows higher tumor uptake while observing more favorable background clearance. As compared to the respective monomer, the higher affinity and prolonged tumor retention additionally represent promising features and warrant further evaluation regarding 68Ga-PET imaging of PSMA expression.
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    25. 25
      Eder, M.; Schafer, M.; Bauder-Wust, U.; Hull, W. E.; Wangler, C.; Mier, W.; Haberkorn, U.; Eisenhut, M. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging Bioconjugate Chem. 2012, 23, 688– 697
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      68Ga-Complex Lipophilicity and the Targeting Property of a Urea-Based PSMA Inhibitor for PET Imaging
      Eder, Matthias; Schaefer, Martin; Bauder-Wuest, Ulrike; Hull, William-Edmund; Waengler, Carmen; Mier, Walter; Haberkorn, Uwe; Eisenhut, Michael
      Bioconjugate Chemistry (2012), 23 (4), 688-697CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      Urea-based inhibitors of the prostate-specific membrane antigen (PSMA) represent low-mol.-wt. pepidomimetics showing the ability to image PSMA-expressing prostate tumors. The highly efficient, acyclic Ga(III) chelator N,N'-bis [2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N'- diacetic acid (HBED-CC) was introduced as a lipophilic side chain into the hydrophilic pharmacophore Glu-NH-CO-NH-Lys which was found favorable to interact with the PSMA "active binding site". This report describes the syntheses, in vitro binding analyses, and biodistribution data of the radiogallium labeled PSMA inhibitor Glu-NH-CO-NH-Lys(Ahx)-HBED-CC in comparison to the corresponding DOTA conjugate. The binding properties were analyzed using competitive cell binding and enzyme-based assays followed by internalization expts. Compared to the DOTA-conjugate, the HBED-CC deriv. showed reduced unspecific binding and considerable higher specific internalization in LNCaP cells. The 68Ga complex of the HBED-CC ligand exhibited higher specificity for PSMA expressing tumor cells resulting in improved in vivo properties. 68Ga labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC showed fast blood and organ clearances, low liver accumulation, and high specific uptake in PSMA expressing organs and tumor. It could be demonstrated that the PET-imaging property of a urea-based PSMA inhibitor could significantly be improved with HBED-CC.
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    26. 26
      Banerjee, S. R.; Pullambhatla, M.; Byun, Y.; Nimmagadda, S.; Green, G.; Fox, J. J.; Horti, A.; Mease, R. C.; Pomper, M. G. 68Ga-labeled inhibitors of prostate-specific membrane antigen (PSMA) for imaging prostate cancer J. Med. Chem. 2010, 53, 5333– 5341
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      26
      68Ga-Labeled Inhibitors of Prostate-Specific Membrane Antigen (PSMA) for Imaging Prostate Cancer
      Banerjee, Sangeeta Ray; Pullambhatla, Mrudula; Byun, Youngjoo; Nimmagadda, Sridhar; Green, Gilbert; Fox, James J.; Horti, Andrew; Mease, Ronnie C.; Pomper, Martin G.
      Journal of Medicinal Chemistry (2010), 53 (14), 5333-5341CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Gallium-68 is a generator-produced radionuclide for positron emission tomog. (PET) that is being increasingly used for radiolabeling of tumor-targeting peptides. Compds. [68Ga]3 and [68Ga]6 are high-affinity urea-based inhibitors of the prostate-specific membrane antigen (PSMA) that were synthesized in decay-uncorrected yields ranging from 60% to 70% and radiochem. purities of more than 99%. Compd. [68Ga]3 demonstrated 3.78 ± 0.90% injected dose per g of tissue (%ID/g) within PSMA+ PIP tumor at 30 min postinjection, while [68Ga]6 showed a 2 h PSMA+ PIP tumor uptake value of 3.29 ± 0.77 %ID/g. Target (PSMA+ PIP) to nontarget (PSMA- flu) ratios were 4.6 and 18.3, resp., at those time points. Both compds. delineated tumor clearly by small animal PET. The urea series of imaging agents for PSMA can be radiolabeled with 68Ga, a cyclotron-free isotope useful for clin. PET studies, with maintenance of target specificity.
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    27. 27
      Banerjee, S. R.; Pullambhatla, M.; Shallal, H.; Lisok, A.; Mease, R. C.; Pomper, M. G. A Modular Strategy to Prepare Multivalent Inhibitors of Prostate-Specific Membrane Antigen (PSMA) Oncotarget 2011, 2, 1244– 1253
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      27
      A modular strategy to prepare multivalent inhibitors of prostate-specific membrane antigen (PSMA)
      Banerjee Sangeeta Ray; Pullambhatla Mrudula; Shallal Hassan; Lisok Ala; Mease Ronnie C; Pomper Martin G
      Oncotarget (2011), 2 (12), 1244-53 ISSN:.
      We have developed a modular scaffold for preparing high-affinity, homo-multivalent inhibitors of the prostate-specific membrane antigen (PSMA) for imaging and therapy of prostate cancer (PCa). Our system contains a lysine-based (μ-, e-) dialkyne residue for incorporating a PSMA binding Lys-Glu urea motif exploiting click chemistry and a second lysine residue for subsequent modification with an imaging or therapeutic moiety. The utility of the multivalent scaffold was examined by synthesizing bivalent compounds 2 and 3 and comparing them with the monovalent analog 1. Determination of inhibition constants (Ki) revealed that bivalent 2 (0.2 nM) and 3 (0.08 nM) are significantly more potent (~ 5 fold and ~ 11 fold, respectively) inhibitors of PSMA than monovalent 1 (0.9 nM). A single photon emission computed tomography (SPECT)-CT imaging study of [111In]3 demonstrated high and specific uptake in PSMA+ PC-3 PIP tumor until at least 48 h post-injection, with rapid clearance from non-target tissues, including kidney. A biodistribution study revealed that [111In]3 demonstrated 34.0 ± 7.5 percent injected dose per gram of tissue in PSMA+ tumor at 24 h post-injection and was capable of generating target-to-non-target ratios of ~ 379 in PSMA+ PC-3 PIP tumors vs. isogenic PSMA-negative PC3-flu tumors in vivo. The click chemistry approach affords a convenient strategy toward multivalent PSMA inhibitors of enhanced affinity and superior pharmacokinetics for imaging.
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    28. 28
      Banerjee, S. R.; Pullambhatla, M.; Byun, Y.; Nimmagadda, S.; Foss, C. A.; Green, G.; Fox, J. J.; Lupold, S. E.; Mease, R. C.; Pomper, M. G. Sequential SPECT and optical imaging of experimental models of prostate cancer with a dual modality inhibitor of the prostate-specific membrane antigen Angew. Chem. 2011, 50, 9167– 9170
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    29. 29
      Chen, Z.; Penet, M. F.; Nimmagadda, S.; Li, C.; Banerjee, S. R.; Winnard, P. T., Jr.; Artemov, D.; Glunde, K.; Pomper, M. G.; Bhujwalla, Z. M. PSMA-targeted theranostic nanoplex for prostate cancer therapy ACS Nano 2012, 6, 7752– 7762
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      29
      PSMA-Targeted Theranostic Nanoplex for Prostate Cancer Therapy
      Chen, Zhihang; Penet, Marie-France; Nimmagadda, Sridhar; Li, Cong; Banerjee, Sangeeta R.; Winnard, Paul T.; Artemov, Dmitri; Glunde, Kristine; Pomper, Martin G.; Bhujwalla, Zaver M.
      ACS Nano (2012), 6 (9), 7752-7762CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Theranostic imaging, where diagnosis is combined with therapy, is particularly suitable for a disease that is as complex as cancer, esp. now that genomic and proteomic profiling can provide an extensive "fingerprint" of each tumor. With such information, theranostic agents can be designed to personalize treatment and minimize damage to normal tissue. Here we have developed a nanoplex platform for theranostic imaging of prostate cancer (PCa). In these proof-of-principle studies, a therapeutic nanoplex contg. multimodal imaging reporters was targeted to prostate-specific membrane antigen (PSMA), which is expressed on the cell surface of castrate-resistant PCa. The nanoplex was designed to deliver small interfering RNA (siRNA) along with a prodrug enzyme to PSMA-expressing tumors. Each component of the nanoplex was carefully selected to evaluate its diagnostic aspect of PSMA imaging and its therapeutic aspects of siRNA-mediated down-regulation of a target gene and the conversion of a prodrug to cytotoxic drug, using noninvasive multimodality imaging. Studies performed using two variants of human PC3-PCa cells and tumors, one with high PSMA expression level and another with negligible expression levels, demonstrated PSMA-specific uptake. In addn., down-regulation of the selected siRNA target, choline kinase (Chk), and the conversion of the nontoxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU) were also demonstrated with noninvasive imaging. The nanoplex was well-tolerated and did not induce liver or kidney toxicity or a significant immune response. The nanoplex platform described can be easily modified and applied to different cancers, receptors, and pathways to achieve theranostic imaging, as a single agent or in combination with other treatment modalities.
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    30. 30
      Hao, G.; Kumar, A.; Dobin, T.; Oz, O. K.; Hsieh, J. T.; Sun, X. A multivalent approach of imaging probe design to overcome an endogenous anion binding competition for noninvasive assessment of prostate specific membrane antigen Mol. Pharmacol. 2013, 10, 2975– 2985
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      There is no corresponding record for this reference.
    31. 31
      Banerjee, S. R.; Pullambhatla, M.; Byun, Y.; Nimmagadda, S.; Baidoo, K. E.; Brechbiel, M. W.; Mease, R. C.; Pomper, M. G. Preclinical Evaluation of 86Y-Labeled Inhibitors of Prostate Specific Membrane Antigen. J. Labelled Compd. Radiopharm. 2011, 54, Suppl S1, p S65.
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      There is no corresponding record for this reference.
    32. 32
      Holland, J. P.; Divilov, V.; Bander, N. H.; Smith-Jones, P. M.; Larson, S. M.; Lewis, J. S. 89Zr–DFO–J591 for immunoPET of prostate-specific membrane antigen expression in vivo J. Nucl. Med. 2010, 51, 1293– 1300
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      There is no corresponding record for this reference.
    33. 33
      Viola-Villegas, N.; Evans, H.; Bartlett, D.; Wu, A.; Lewis, J. Preclinical development of Zr-89 labeled anti-PSMA minibody and cys-diabody J Nucl. Med. Meet. Abstr. 2012, 53, 347
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      There is no corresponding record for this reference.
    34. 34
      Ray Banerjee, S.; Pullambhatla, M.; Foss, C. A.; Falk, A.; Byun, Y.; Nimmagadda, S.; Mease, R. C.; Pomper, M. G. Effect of chelators on the pharmacokinetics of (99m)Tc-labeled imaging agents for the prostate-specific membrane antigen (PSMA) J. Med. Chem. 2013, 56, 6108– 6121
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      34
      Effect of Chelators on the Pharmacokinetics of 99mTc-Labeled Imaging Agents for the Prostate-Specific Membrane Antigen (PSMA)
      Ray Banerjee, Sangeeta; Pullambhatla, Mrudula; Foss, Catherine A.; Falk, Alexander; Byun, Youngjoo; Nimmagadda, Sridhar; Mease, Ronnie C.; Pomper, Martin G.
      Journal of Medicinal Chemistry (2013), 56 (15), 6108-6121CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Technetium-99m, the most commonly used radionuclide in nuclear medicine, can be attached to biol. important mols. through a variety of chelating agents, the choice of which depends upon the imaging application. The prostate-specific membrane antigen (PSMA) is increasingly recognized as an important target for imaging and therapy of prostate cancer (PCa). Three different 99mTc-labeling methods were employed to investigate the effect of the chelator on the biodistribution and PCa tumor uptake profiles of 12 new urea-based PSMA-targeted radiotracers. This series includes hydrophilic ligands for radiolabeling with the [99mTc(CO)3]+ core (L8-L10), traditional NxSy-based chelating agents with varying charge and polarity for the 99mTc-oxo core (L11-L18), and a 99mTc-organohydrazine-labeled radioligand (L19). 99mTc(I)-Tricarbonyl-labeled [99mTc]L8 produced the highest PSMA+ PC3 PIP to PSMA- PC3 flu tumor ratios and demonstrated the lowest retention in normal tissues including kidney after 2 h. These results suggest that choice of chelator is an important pharmacokinetic consideration in the development of 99mTc-labeled radiopharmaceuticals targeting PSMA.
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    35. 35
      Wadas, T. J.; Wong, E. H.; Weisman, G. R.; Anderson, C. J. Copper chelation chemistry and its role in copper radiopharmaceuticals Curr. Pharm. Des. 2007, 13, 3– 16
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      35
      Copper chelation chemistry and its role in copper radiopharmaceuticals
      Wadas, T. J.; Wong, E. H.; Weisman, G. R.; Anderson, C. J.
      Current Pharmaceutical Design (2007), 13 (1), 3-16CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
      A review. Mol. imaging is an important scientific discipline that plays a major role in clin. medicine and pharmaceutical development. While several imaging modalities including x-ray computed tomog. and magnetic resonance imaging generate high-resoln. anatomical images, positron emission tomog. (PET) and single photon emission computed tomog. offer insight into the physiol. processes that occur within a living organism. Of these two nuclear medicine imaging techniques, PET has advantages with respect to sensitivity and resoln., and this has led to the prodn. and development of many positron emitting radionuclides that include non-traditional radionuclides of the transition metals. Copper-64 (t1/2 = 12.7 h, β+: 17.4%, Eβ+max = 656 keV; β-: 39%, Eβ-max = 573 keV) has emerged as an important positron emitting radionuclide that has the potential for use in diagnostic imaging and radiotherapy. However, 64Cu must be delivered to the living system as a stable complex that is attached to a biol. targeting mol. for effective imaging and therapy. Therefore, significant research has been devoted to the development of ligands that can stably chelate 64Cu. This review discusses the necessary characteristics of an effective 64Cu chelator, while highlighting the development and evaluation of 64Cu-complexes attached to biol.-targeted ligands.
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    36. 36
      Connett, J. M.; Anderson, C. J.; Guo, L. W.; Schwarz, S. W.; Zinn, K. R.; Rogers, B. E.; Siegel, B. A.; Philpott, G. W.; Welch, M. J. Radioimmunotherapy with a 64Cu-labeled monoclonal antibody: a comparison with 67Cu Proc. Natl. Acad. Sci. U. S. A. 1996, 93, 6814– 6818
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      Radioimmunotherapy with a 64Cu-labeled monoclonal antibody: a comparison with 67Cu
      Connett, Judith M.; Anderson, Carolyn J.; Guo, Li-Wu; Schwarz, Sally W.; Zinn, Kurt R.; Rogers, Buck E.; Siegel, Barry A.; Philpott, Gordon; Welch, Michael J.
      Proceedings of the National Academy of Sciences of the United States of America (1996), 93 (13), 6814-6818CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      67Cu (t1/2 = 62 h) has demonstrated potential as a radionuclide for radioimmunotherapy, but limited availability severely restricts its widespread use. 64Cu (t1/2 = 12.8 h) has been shown to have comparable effectiveness in vitro and in vivo. The present study was undertaken to examine the therapeutic potential of 64Cu- and 67Cu-bromoacetamidobenzyl-1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (BAT)-2-iminothiolane (2IT)-1A3 (1A3 is a mouse anti-human colorectal cancer mAb) for treatment of GW39 human colon carcinoma carried in hamster thighs. Hamsters were injected with 64Cu- or 67C-BAT-2IT-1A3 or Cu-labeled nonspecific IgG (MOPC) or saline. Hamsters were killed 6-7 mo after therapy or when tumors were ≥10 g. Of the hamsters with small tumors (mean wt. 0.43 ± 0.25 g), 87.5% were disease-free 7 mo after treatment with 2 mCi (1 Ci = 37 GBq) of 64Cu-BAT-2IT-1A3 or 0.4 mCi of 67Cu-BAT-2IT-1A3. The mean tumor doses at these activities of 64Cu- and 67Cu-BAT-2IT-1A3 were 586 and 1269 rad (1 rad = 0.01 Gy), resp. In contrast, 76% of hamsters treated with 2 mCi of 64Cu-BAT-2IT-MOPC or 0.4 mCi of 67Cu-BAT-2IT-MOPC had to be killed before 6 mo because of tumor regrowth. When hamsters with larger tumors (mean wt. 0.66 ± 0.11 g) were treated with 64Cu- or 67Cu-BAT-2IT-1A3, survival was extended compared with controls, but only one animal remained tumor-free to 6 mo. These results demonstrate that 64Cu- and 67Cu-BAT-2IT-1A3 given in a single administered dose can eradicate small tumors without significant host toxicity, but addnl. strategies to deliver higher tumor doses will be needed for larger tumors.
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    37. 37
      Blower, P. J.; Lewis, J. S.; Zweit, J. Copper radionuclides and radiopharmaceuticals in nuclear medicine Nucl. Med. Biol. 1996, 23, 957– 980
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      37
      Copper radionuclides and radiopharmaceuticals in nuclear medicine
      Blower, Philip J.; Lewis, Jason S.; Zweit, Jamal
      Nuclear Medicine and Biology (1996), 23 (8), 957-980CODEN: NMBIEO; ISSN:0883-2897. (Elsevier)
      The chem., radiochem., radiobiol., and radiopharmacol. of radiopharmaceuticals contg. copper radionuclides are reviewed, with 210 refs. Copper radionuclides offer application in positron emission tomog., targeted radiotherapy, and single photon imaging. The chem. of copper is relatively simple and well-suited to radiopharmaceutical application. Current radiopharmaceuticals include biomols. labeled via bifunctional chelators primarily based on cyclic polyaminocarboxylates and polyamines, and pyruvaldehyde-bis(N4-methylthiosemicarbazone) (PTSM) and its analogs. The chem. of copper, of which only a fraction has yet been exploited, is likely to be applied more fully in the future.
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    38. 38
      Guo, Y.; Parry, J. J.; Laforest, R.; Rogers, B. E.; Anderson, C. J. The role of p53 in combination radioimmunotherapy with 64Cu–DOTA–cetuximab and cisplatin in a mouse model of colorectal cancer J. Nucl. Med. 2013, 54, 1621– 1629
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      There is no corresponding record for this reference.
    39. 39
      Donnelly, P. S. The role of coordination chemistry in the development of copper and rhenium radiopharmaceuticals Dalton Trans. 2011, 40, 999– 1010
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      There is no corresponding record for this reference.
    40. 40
      Smith, S. V. Molecular imaging with copper-64 J. Inorg. Biochem. 2004, 98, 1874– 1901
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      40
      Molecular imaging with copper-64
      Smith, Suzanne V.
      Journal of Inorganic Biochemistry (2004), 98 (11), 1874-1901CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier B.V.)
      A review. Mol. imaging is expected to change the face of drug discovery and development. The ability to link imaging to biol. for guiding therapy should improve the rate at which novel imaging technologies, probes, contrast agents, drugs and drug delivery systems can be transferred into clin. practice. Nuclear medicine imaging, in particular, positron emission tomog. (PET) allows the detection and monitoring of a variety of biol. and pathophysiol. processes, at tracer quantities of the radiolabeled target agents, and at doses free from pharmacol. effects. In the field of drug discovery and development, the use of radiotracers for radiolabelling target agents has now become one of the essential tools in identifying, screening and development of new target agents. In this regard, 64Cu (t1/2 = 12.7 h) has been identified as an emerging PET isotope. Its half-life is sufficiently long for radiolabelling a range of target agents and its ease of prodn. and adaptable chem. make it an excellent radioisotope for use in mol. imaging. This review describes recent advances, in the routes of 64Cu prodn., design and application of bi-functional ligands for use in radiolabelling with 64/67Cu2+, and their significance and anticipated impact on the field of mol. imaging and drug development.
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    41. 41
      Wadas, T. J.; Wong, E. H.; Weisman, G. R.; Anderson, C. J. Molecular imaging of cancer with copper-64 radiopharmaceuticals and positron emission tomography (PET) Chem. Rev. 2010, 110, 2858– 2902
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      41
      Coordinating Radiometals of Copper, Gallium, Indium, Yttrium, and Zirconium for PET and SPECT Imaging of Disease
      Wadas, Thaddeus J.; Wong, Edward H.; Weisman, Gary R.; Anderson, Carolyn J.
      Chemical Reviews (Washington, DC, United States) (2010), 110 (5), 2858-2902CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review.
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    42. 42
      Shokeen, M.; Anderson, C. J. Coordinating radiometals of copper, gallium, indium, yttrium, and zirconium for PET and SPECT imaging of disease Acc. Chem. Res. 2009, 110, 832– 841
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      There is no corresponding record for this reference.
    43. 43
      De Silva, R. A.; Peyre, K.; Pullambhatla, M.; Fox, J. J.; Pomper, M. G.; Nimmagadda, S. Imaging CXCR4 expression in human cancer xenografts: evaluation of monocyclam 64Cu–AMD3465 J. Nucl. Med. 2011, 52, 986– 993
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      There is no corresponding record for this reference.
    44. 44
      Yuan, H.; Schroeder, T.; Bowsher, J. E.; Hedlund, L. W.; Wong, T.; Dewhirst, M. W. Intertumoral differences in hypoxia selectivity of the PET imaging agent 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) J. Nucl. Med. 2006, 47, 989– 998
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      44
      Intertumoral differences in hypoxia selectivity of the PET imaging agent 64Cu(II)-diacetyl-Bis(N4-methylthiosemicarbazone)
      Yuan, Hong; Schroeder, Thies; Bowsher, James E.; Hedlund, Laurence W.; Wong, Terence; Dewhirst, Mark W.
      Journal of Nuclear Medicine (2006), 47 (6), 989-998CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)
      Cu-Diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) is a recently developed PET imaging agent for tumor hypoxia. However, its accuracy and reliability for measuring hypoxia have not been fully characterized in vivo. The aim of this study was to evaluate 64Cu-ATSM as a hypoxia PET marker by comparing autoradiog. distributions of 64Cu-ATSM with a well-established hypoxia marker drug, EF5. Methods: R3230 mammary adenocarcinomas (R3230Ac), fibrosarcomas (FSA), and 9L gliomas (9L) were used in the study. EF5 and Hoechst 33342, a vascular perfusion marker, were administered to the animal for immunohistochem. anal. 64Cu-ATSM microPET and autoradiog. were performed on the same animal. The tumor-to-muscle ratio (T/M ratio) and standardized uptake values (SUVs) were characterized for these 3 different types of tumors. Five types of images-microPET, autoradiog., EF5 immunostaining, Hoechst fluorescence vascular imaging, and hematoxylin-andeosin histol.-were superimposed, evaluated, and compared. Results: A significantly higher T/M ratio and SUV were seen for FSA compared with R3230Ac and 9L. Spatial correlation anal. between 64Cu-ATSM autoradiog. and EF5 immunostained images varied between the 3 tumor types. There was close correlation of 64Cu-ATSM uptake and hypoxia in R3230Ac and 9L tumors but not in FSA tumors. Interestingly, elevated 64Cu-ATSM uptake was obsd. in well-perfused areas in FSA, indicating a correlation between 64Cu-ATSM uptake and vascular perfusion as opposed to hypoxia. The same relationship was obsd. with 2 other hypoxia markers, pimonidazole and carbonic anhydrase IX, in FSA tumors. Breathing carbogen gas significantly decreased the hypoxia level measured by EF5 staining in FSA-bearing rats but not the uptake of 64Cu-ATSM. These results indicate that some other 64Cu-ATSM retention mechanisms, as opposed to hypoxia, are involved in this type of tumor. Conclusion: To our knowledge, this study is the first comparison between 64Cu-ATSM uptake and immunohistochem. in these 3 tumors. Although we have shown that 64Cu-ATSM is a valid PET hypoxia marker in some tumor types, but not for all, this tumor type-dependent hypoxia selectivity of 64Cu-ATSM challenges the use of 64Cu-ATSM as a universal PET hypoxia marker. Further studies are needed to define retention mechanisms for this PET marker.
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    45. 45
      Liu, Z.; Li, Z. B.; Cao, Q.; Liu, S.; Wang, F.; Chen, X. Small-animal PET of tumors with (64)Cu-labeled RGD–bombesin heterodimer J. Nucl. Med. 2009, 50, 1168– 1177
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      There is no corresponding record for this reference.
    46. 46
      Dumont, R. A.; Deininger, F.; Haubner, R.; Maecke, H. R.; Weber, W. A.; Fani, M. Novel (64)Cu- and (68)Ga-labeled RGD conjugates show improved PET imaging of alpha(nu)beta(3) integrin expression and facile radiosynthesis J. Nucl. Med. 2011, 52, 1276– 1284
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      There is no corresponding record for this reference.
    47. 47
      Fani, M.; Del Pozzo, L.; Abiraj, K.; Mansi, R.; Tamma, M. L.; Cescato, R.; Waser, B.; Weber, W. A.; Reubi, J. C.; Maecke, H. R. PET of somatostatin receptor-positive tumors using 64Cu– and 68Ga–somatostatin antagonists: the chelate makes the difference J. Nucl. Med. 2011, 52, 1110– 1118
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      47
      PET of somatostatin receptor-positive tumors using 64Cu- and 68Ga-somatostatin antagonists: the chelate makes the difference
      Fani, Melpomeni; Del Pozzo, Luigi; Abiraj, Keelara; Mansi, Rosalba; Tamma, Maria Luisa; Cescato, Renzo; Waser, Beatrice; Weber, Wolfgang A.; Reubi, Jean Claude; Maecke, Helmut R.
      Journal of Nuclear Medicine (2011), 52 (7), 1110-1118CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)
      Somatostatin-based radiolabeled peptides have been successfully introduced into the clinic for targeted imaging and radionuclide therapy of somatostatin receptor (sst)-pos. tumors, esp. of subtype 2 (sst2). The clin. used peptides are exclusively agonists. Recently, we showed that radiolabeled antagonists may be preferable to agonists because they showed better pharmacokinetics, including higher tumor uptake. Factors detg. the performance of radioantagonists have only scarcely been studied. Here, we report on the development and evaluation of four 64Cu or 68Ga radioantagonists for PET of sst2-pos. tumors. Methods: The novel antagonist p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2 (LM3) was coupled to 3 macrocyclic chelators, namely 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), 1,4,7-triazacyclononane, 1-glutaric acid-4,7-acetic acid (NODAGA), and DOTA. 64/natCu- and 68/natGa-NODAGA-LM3 were prepd. at room temp., and 64/natCu-CB-TE2A-LM3 and 68/natGa-DOTA-LM3 were prepd. at 95°C. Binding affinity and antagonistic properties were detd. with receptor autoradiog. and immunofluorescence microscopy using human embryonic kidney (HEK)-sst2 cells. In vitro internalization and dissocn. was evaluated using the same cell line. Biodistribution and small-animal PET studies were performed with HEK-sst2 xenografts. Results: All metallopeptides demonstrated antagonistic properties. The affinities depend on chelator and radiometal and vary about 10-fold; 68/natGa-NODAGA-LM3 has the lowest half maximal inhibitory concn. (1.3 ± 0.3 nmol/L). The biodistribution studies show impressive tumor uptake at 1 h after injection, particularly of 64Cu- and 68Ga-NODAGA-LM3 (∼40 percentage injected dose per g of tissue [%ID/g]), which were proven to be specific. Background clearance was fast and the tumor washout relatively slow for 64Cu-NODAGA-LM3 (∼15 %ID/g, 24 h after injection) and almost negligible for 64Cu-CB-TE2A-LM3 (26.9 ± 3.3 %ID/g and 21.6 ± 2.1 %ID/g, 4 and 24 h after injection, resp.). Tumor-to-normal-tissue ratios were significantly higher for 64Cu-NODAGA-LM3 than for 64Cu-CB-TE2A-LM3 (tumor-to-kidney, 12.8 ± 3.6 and 1.7 ± 0.3, resp.; tumor-to-muscle, 1,342 ± 115 and 75.2 ± 8.5, resp., at 24 h, P < 0.001). Small-animal PET shows clear tumor localization and high image contrast, esp. for 64Cu- and 68Ga-NODAGA-LM3. Conclusion: This article demonstrates the strong dependence of the affinity and pharmacokinetics of the somatostatin-based radioantagonists on the chelator and radiometal. 64Cu- and 68Ga-NODAGA-LM3 and 64Cu-CB-TE2A-LM3 are promising candidates for clin. translation because of their favorable pharmacokinetics and the high image contrast on PET scans.
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    48. 48
      Liu, Z.; Li, Z. B.; Cao, Q.; Liu, S.; Wang, F.; Chen, X.; Small-animal, P. E. T. of tumors with (64)Cu-labeled RGD–bombesin heterodimer J. Nucl. Med. 2009, 50, 1168– 1177
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      There is no corresponding record for this reference.
    49. 49
      Rockey, W. M.; Huang, L.; Kloepping, K. C.; Baumhover, N. J.; Giangrande, P. H.; Schultz, M. K. Synthesis and radiolabeling of chelator–RNA aptamer bioconjugates with copper-64 for targeted molecular imaging Bioorg. Med. Chem. 2011, 19, 4080– 4090
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      There is no corresponding record for this reference.
    50. 50
      Hou, G. L.; Li, Y. H.; Zhang, Z. L.; Xiong, Y. H.; Chen, X. F.; Yao, K.; Liu, Z. W.; Han, H.; Qin, Z. K.; Zhou, F. J. A modified technique for neourethral anastomosis in orthotopic neobladder reconstruction Urology 2009, 74, 1145– 1149
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      There is no corresponding record for this reference.
    51. 51
      Cooper, M. S.; Ma, M. T.; Sunassee, K.; Shaw, K. P.; Williams, J. D.; Paul, R. L.; Donnelly, P. S.; Blower, P. J. Comparison of (64)Cu-complexing bifunctional chelators for radioimmunoconjugation: labeling efficiency, specific activity, and in vitro/in vivo stability Bioconjugate Chem. 2012, 23, 1029– 1039
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      Comparison of 64Cu-Complexing Bifunctional Chelators for Radioimmunoconjugation: Labeling Efficiency, Specific Activity, and in Vitro/in Vivo Stability
      Cooper, Maggie S.; Ma, Michelle T.; Sunassee, Kavitha; Shaw, Karen P.; Williams, Jennifer D.; Paul, Rowena L.; Donnelly, Paul S.; Blower, Philip J.
      Bioconjugate Chemistry (2012), 23 (5), 1029-1039CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      High radiolabeling efficiency, preferably to high specific activity, and good stability of the radioimmunoconjugate are essential features for a successful immunoconjugate for imaging or therapy. In this study, the radiolabeling efficiency, in vitro stability, and biodistribution of immunoconjugates with eight different bifunctional chelators labeled with 64Cu were compared. The anti-CD20 antibody, rituximab, was conjugated to four macrocyclic bifunctional chelators (p-SCN-Bn-DOTA, p-SCN-Bn-Oxo-DO3A, p-SCN-NOTA, and p-SCN-PCTA), three DTPA derivs. (p-SCN-Bn-DTPA, p-SCN-CHX-A''-DTPA, and ITC-2B3M-DTPA), and a macrobicyclic hexamine (sarcophagine) chelator (sar-CO2H) = (1-NH2-8-NHCO(CH2)3CO2H)sar where sar = sarcophagine = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane. Radiolabeling efficiency under various conditions, in vitro stability in serum at 37 °C, and in vivo biodistribution and imaging in normal mice over 48 h were studied. All chelators except sar-CO2H were conjugated to rituximab by thiourea bond formation with an av. of 4.9 ± 0.9 chelators per antibody mol. Sar-CO2H was conjugated to rituximab by amide bond formation with 0.5 chelators per antibody mol. Efficiencies of 64Cu radiolabeling were dependent on the concn. of immunoconjugate. Notably, the 64Cu-NOTA-rituximab conjugate demonstrated the highest radiochem. yield (95%) under very dil. conditions (31 nM NOTA-rituximab conjugate). Similarly, sar-CO-rituximab, contg. 1/10th the no. of chelators per antibody compared to that of other conjugates, retained high labeling efficiency (98%) at an antibody concn. of 250 nM. In contrast to the radioimmunoconjugates contg. DTPA derivs., which demonstrated poor serum stability, all macrocyclic radioimmunoconjugates were very stable in serum with <6% dissocn. of 64Cu over 48 h. In vivo biodistribution profiles in normal female Balb/C mice were similar for all the macrocyclic radioimmunoconjugates with most of the activity remaining in the blood pool up to 48 h. While all the macrocyclic bifunctional chelators are suitable for mol. imaging using 64Cu-labeled antibody conjugates, NOTA and sar-CO2H show significant advantages over the others in that they can be radiolabeled rapidly at room temp., under dil. conditions, resulting in high specific activity.
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    52. 52
      Moi, M. K.; Meares, C. F.; McCall, M. J.; Cole, W. C.; DeNardo, S. J. Copper chelates as probes of biological systems: stable copper complexes with a macrocyclic bifunctional chelating agent Anal. Biochem. 1985, 148, 249– 253
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      Copper chelates as probes of biological systems: stable copper complexes with a macrocyclic bifunctional chelating agent
      Moi, Min K.; Meares, Claude F.; McCall, Michael J.; Cole, William C.; DeNardo, Sally J.
      Analytical Biochemistry (1985), 148 (1), 249-53CODEN: ANBCA2; ISSN:0003-2697.
      The synthesis of a new bifunctional metal chelator, 6-(p-bromoacetamidobenzyl)-1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA) is described, which can be covalently attached to proteins and which binds Cu stably in human serum under physiol. conditions. 67Cu chelates of p-nitrobenzyl-TETA, p-nitrobenzyl-EDTA, diethylenetriaminepentaacetic acid (DTPA)-N-butylamide, and DTPA, as well as conjugates of Cu chelates with mouse monoclonal antibody lym-1 were also prepd. and their stability in human serum was examd. In contrast to TETA, Cu chelates prepd. from analogs of EDTA or DTPA were not stable to prolonged incubation in human serum and rapidly lost Cu to serum albumin.
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    53. 53
      Jones-Wilson, T. M.; Deal, K. A.; Anderson, C. J.; McCarthy, D. W.; Kovacs, Z.; Motekaitis, R. J.; Sherry, A. D.; Martell, A. E.; Welch, M. J. The in vivo behavior of copper-64-labeled azamacrocyclic complexes Nucl. Med. Biol. 1998, 25, 523– 530
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      The in vivo behavior of copper-64-labeled azamacrocyclic complexes
      Jones-Wilson, Teresa M.; Deal, Kim A.; Anderson, Carolyn J.; McCarthy, Deborah W.; Kovacs, Zoltan; Motekaitis, Ramunas J.; Sherry, A. Dean; Martell, Arthur E.; Welch, Michael J.
      Nuclear Medicine and Biology (1998), 25 (6), 523-530CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Science Inc.)
      The use of copper radioisotopes in imaging and therapy applications has created a greater need for bifunctional chelates (BFCs) for complexing copper radioisotopes to biomols. It has been demonstrated that the charge and lipophilicity of the Cu-BFC complex has a significant effect on the in vivo behavior of the radiolabeled Cu-BFC-biomol. conjugate. To evaluate the effects of charge, stability, and macrocyclic backbone size on the biol. behavior of 64Cu complexes, a series of macrocyclic 64Cu complexes have been prepd., and the biodistributions of these agents were evaluated in normal Sprague-Dawley rats. Two macrocyclic backbones, dodecane and tetradecane, were evaluated; cyclen, DOTA, and DO2A were dodecane backbone derivs., and cyclam, TETA, and et-cyclam were tetradecane backbone derivs. The biodistributions of the 64Cu-labeled complexes correlated with differences in the size of the macrocycle backbone and the formal charge of the complex. All compds. showed uptake and clearance through the liver and kidneys; however, the pos. charged 64Cu complexes showed significantly higher uptake in both of these organs than did the neg. charged or neutral complexes. 64Cu-TETA, a neg. charged complex with the tetradecane backbone, had the most efficient clearance by 24 h' postinjection. These data suggest that neg. charged complexes may have more favorable clearance properties when used as BFCs.
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    54. 54
      Garrison, J. C.; Rold, T. L.; Sieckman, G. L.; Figueroa, S. D.; Volkert, W. A.; Jurisson, S. S.; Hoffman, T. J. In vivo evaluation and small-animal PET/CT of a prostate cancer mouse model using 64Cu bombesin analogs: side-by-side comparison of the CB-TE2A and DOTA chelation systems J. Nucl. Med. 2007, 48, 1327– 1337
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      In vivo evaluation and small-animal PET/CT of a prostate cancer mouse model using 64Cu bombesin analogs: side-by-side comparison of the CB-TE2A and DOTA chelation systems
      Garrison, Jered C.; Rold, Tammy L.; Sieckman, Gary L.; Figueroa, Said Daibes; Volkert, Wynn A.; Jurisson, Silvia S.; Hoffman, Timothy J.
      Journal of Nuclear Medicine (2007), 48 (8), 1327-1337CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)
      The BB2 receptor subtype, of the bombesin family of receptors, has been shown to be highly overexpressed in a variety of human tumors, including prostate cancer. Bombesin (BBN), a 14-amino acid peptide, has been shown to target the BB2 receptor with high affinity. 64Cu (half-life = 12.7 h, β+: 18%, Eβ+max = 653 keV; β-: 37%, Eβ-max = 578 keV) is a radioisotope that has clin. potential for application in both diagnostic imaging and radionuclide therapy. Recently, new chelation systems such as 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A) have been reported to significantly stabilize the 64Cu radiometal in vivo. The increased stability of the 64Cu-CB-TE2A chelate complex has been shown to significantly reduce nontarget retention compared with tetraazamacrocycles such as 1,4,7,10-tetraazacyclodoadecane-N,N',N",N'"-tetraacetic acid (DOTA). The aim of this study was to det. whether the CB-TE2A chelation system could significantly improve the in vivo stability of 64Cu bombesin analogs. The study directly compares 64Cu bombesin analogs using the CB-TE2A and DOTA chelation systems in a prostate cancer xenograft SCID (severely compromised immunodeficient) mouse model. Methods: The CB-TE2A-8-AOC-BBN(7-14)NH2 and DOTA-8-AOC-BBN(7-14) NH2 conjugates were synthesized and radiolabeled with 64Cu. The receptor-binding affinity and internalization profile of each metalated conjugate was evaluated using PC-3 cells. Pharmacokinetic and small-animal PET/CT studies were performed using female SCID mice bearing PC-3 xenografts. Results: In vivo BB2 receptor targeting was confirmed by tumor uptake values of 6.95 ± 2.27 and 4.95 ± 0.91 %ID/g (percentage injected dose per g) at the 15-min time point for the 64Cu-CB-TE2A and 64Cu-DOTA radioconjugates, resp. At the 24-h time point, liver uptake was substantially reduced for the 64Cu-CB-TE2A radioconjugate (0.21 ± 0.06 %ID/g) compared with the 64Cu-DOTA radioconjugate (7.80 ± 1.51 %ID/g). The 64Cu-CB-TE2A-8-AOC-BBN(7-14)NH2 radioconjugate demonstrated significant clearance, 98.60 ± 0.28 %ID, from the mouse at 24 h after injection. In contrast, only 67.84 ± 5.43 %ID of the 64Cu activity was excreted using the 64Cu-DOTA-8-AOC-BBN(7-14)NH2 radioconjugate because of nontarget retention. Conclusion: The pharmacokinetic and small-animal PET/CT studies demonstrate significantly improved nontarget tissue clearance for the 64Cu-CB-TE2A8-AOC-BBN(7-14)NH2. This is attributed to the improved in vivo stability of the 64Cu-CB-TE2A chelate complex as compared with the 64Cu-DOTA chelate complex.
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    55. 55
      Sun, X.; Wuest, M.; Weisman, G. R.; Wong, E. H.; Reed, D. P.; Boswell, C. A.; Motekaitis, R.; Martell, A. E.; Welch, M. J.; Anderson, C. J. Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands J. Med. Chem. 2002, 45, 469– 477
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      Radiolabeling and in vivo behavior of copper-64-labeled cross-bridged cyclam ligands
      Sun, Xiankai; Wuest, Melinda; Weisman, Gary R.; Wong, Edward H.; Reed, David P.; Boswell, C. Andrew; Motekaitis, Ramunas; Martell, Arthur E.; Welch, Michael J.; Anderson, Carolyn J.
      Journal of Medicinal Chemistry (2002), 45 (2), 469-477CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Macrocyclic chelators and their metal complexes have widespread applications in the biomedical sciences, including radiopharmaceutical chem. The use of copper radionuclides in radiopharmaceuticals is increasing. Macrocyclic chelators have been found to have enhanced in vivo stability over acyclic chelators such as EDTA and diethylenetriaminepentaacetic acid (DTPA). The currently used chelators of choice for labeling copper radionuclides to biol. mols. are analogs of TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid); however, recent reports have demonstrated evidence of in vivo instability of the radio-Cu(II)-TETA complexes. A new class of structurally reinforced macrocycles, the "cross-bridged" cyclam derivs., form highly stable complexes with Cu(II) that are resistant to dissocn. in strong acid. Here, we evaluate a series of 64Cu(II) cross-bridged macrocyclic complexes for biol. stability and in vivo behavior. The ligands evaluated include the parent ligand, 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (1), and three 4,11-di-pendant arm derivs.: 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (2); 4,11-bis(N,N-diethyl-amidomethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (3); and 4,11-bis(amidoethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (4). Copper-64 formed complexes with ligands 1-4 in high radiochem. yields. The 64Cu-2 complex was neutral, while 64Cu complexes of 1, 3, and 4 were pos. charged. All complexes showed no decompn. in rat serum out to 24 h. Biodistribution expts. in Sprague-Dawley rats indicated that 64Cu-1, -3, and -4 were taken up by the liver and kidney and cleared slowly over 24 h, whereas 64Cu-2 cleared rapidly from all tissues. The rapid clearance of the 64Cu-2 complex from the blood and liver, as well as liver metab. expts. in rats, suggests that it is highly stable in vivo. A bifunctional chelator of 2 is a significant candidate for labeling copper radionuclides to biol. mols. for diagnostic imaging and targeted radiotherapy.
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    56. 56
      Boswell, C. A.; Sun, X.; Niu, W.; Weisman, G. R.; Wong, E. H.; Rheingold, A. L.; Anderson, C. J. Comparative in vivo stability of copper-64-labeled cross-bridged and conventional tetraazamacrocyclic complexes J. Med. Chem. 2004, 47, 1465– 1474
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      Comparative in Vivo Stability of Copper-64-Labeled Cross-Bridged and Conventional Tetraazamacrocyclic Complexes
      Boswell, C. Andrew; Sun, Xiankai; Niu, Weijun; Weisman, Gary R.; Wong, Edward H.; Rheingold, Arnold L.; Anderson, Carolyn J.
      Journal of Medicinal Chemistry (2004), 47 (6), 1465-1474CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The increased use of copper radioisotopes in radiopharmaceutical applications has created a need for bifunctional chelators (BFCs) that form stable radiocopper complexes and allow covalent attachment to biol. mols. The chelators most commonly utilized for labeling copper radionuclides to biomols. are analogs of 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); however, recent reports have communicated the instability of the radio-Cu(II)-TETA complexes in vivo. A class of bicyclic tetraazamacrocycles, the ethylene "cross-bridged" cyclam (CB-cyclam) derivs., form highly kinetically stable complexes with Cu(II) and therefore may be less susceptible to transchelation than their nonbridged analogs in vivo. Herein we report results on the relative biol. stabilities and identification of the resulting radiolabeled metabolites of a series of 64Cu-labeled macrocyclic complexes. Metab. studies in normal rat liver have revealed that the 64Cu complex of 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (64Cu-CB-TE2A) resulted in significantly lower values of protein-assocd. 64Cu than 64Cu-TETA [13 ± 6% vs 75 ± 9% at 4 h]. A similar trend was obsd. for the corresponding cyclen derivs., with the 64Cu complex of 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (64Cu-CB-DO2A) undergoing less transchelation than the 64Cu complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (64Cu-DOTA) [61 ± 14% vs 90.3 ± 0.5% protein assocd. 64Cu at 4 h]. These data indicate that the structurally reinforcing cross-bridge enhances in vivo stability by reducing metal loss to protein in both the cyclam and cyclen cross-bridged 64Cu complexes and that 64Cu-CB-TE2A is superior to 64Cu-CB-DO2A in that regard. These findings further suggest that a bifunctional chelator deriv. of CB-TE2A is a highly desirable alternative for labeling copper radionuclides to biol. mols. for diagnostic imaging and targeted radiotherapy.
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    57. 57
      Sprague, J. E.; Peng, Y.; Sun, X.; Weisman, G. R.; Wong, E. H.; Achilefu, S.; Anderson, C. J. Preparation and biological evaluation of copper-64-labeled tyr3-octreotate using a cross-bridged macrocyclic chelator Clin. Cancer Res. 2004, 10, 8674– 8682
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      Preparation and biological evaluation of copper-64-labeled Tyr3-octreotate using a cross-bridged macrocyclic chelator
      Sprague, Jennifer E.; Peng, Yijie; Sun, Xiankai; Weisman, Gary R.; Wong, Edward H.; Achilefu, Samuel; Anderson, Carolyn J.
      Clinical Cancer Research (2004), 10 (24), 8674-8682CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
      Somatostatin receptors (SSTr) are expressed on many neuroendocrine tumors, and several radiotracers have been developed for imaging these types of tumors. For this reason, peptide analogs of somatostatin have been well characterized. Copper-64 (t1/2 = 12.7 h), a positron emitter suitable for positron emission tomog. (PET) imaging, was shown recently to have improved in vivo clearance properties when chelated by the cross-bridged tetraazamacrocycle 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane (CB-TE2A) compared with 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA). CB-TE2A and TETA were conjugated to the somatostatin analog tyrosine-3-octreotate (Y3-TATE) for evaluation of CB-TE2A as a bifunctional chelator of 64Cu. The in vitro affinity of each compd. for SSTr was detd. using a homologous competitive binding assay. In vivo characteristics of both radiolabeled compds. were examd. in biodistribution and microPET studies of AR42J tumor-bearing rats. Cu-CB-TE2A-Y3-TATE (Kd = 1.7 nmol/L) and Cu-TETA-Y3-TATE (Kd = 0.7 nmol/L) showed similar affinities for AR42J derived SSTr. In biodistribution studies, nonspecific uptake in blood and liver was lower for 64Cu-CB-TE2A-Y3-TATE. Differences increased with time such that, at 4 h, blood uptake was 4.3-fold higher and liver uptake was 2.4-fold higher for 64Cu-TETA-Y3-TATE than for 64Cu-CB-TE2A-Y3-TATE. In addn., 4.4-times greater tumor uptake was detected with 64Cu-CB-TE2A-Y3-TATE than with 64Cu-TETA-Y3-TATE at 4 h postinjection. MicroPET imaging yielded similar results. CB-TE2A appears to be a superior in vivo bifunctional chelator of 64Cu for use in mol. imaging by PET or targeted radiotherapy due to both improved nontarget organ clearance and higher target organ uptake of 64Cu-CB-TE2A-Y3-TATE compared with 64Cu-TETA-Y3-TATE.
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    58. 58
      Ait-Mohand, S.; Fournier, P.; Dumulon-Perreault, V.; Kiefer, G. E.; Jurek, P.; Ferreira, C. L.; Benard, F.; Guerin, B. Evaluation of 64Cu-labeled bifunctional chelate–bombesin conjugates Bioconjugate Chem. 2011, 22, 1729– 1735
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      Evaluation of 64Cu-Labeled Bifunctional Chelate-Bombesin Conjugates
      Ait-Mohand, Samia; Fournier, Patrick; Dumulon-Perreault, Veronique; Kiefer, Garry E.; Jurek, Paul; Ferreira, Cara L.; Benard, Francois; Guerin, Brigitte
      Bioconjugate Chemistry (2011), 22 (8), 1729-1735CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      Several bifunctional chelates (BFCs) were investigated as carriers of 64Cu for PET imaging. The most widely used chelator for 64Cu labeling of BFCs is DOTA (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tretraacetic acid), even though this complex exhibits only moderate in vivo stability. In this study, we prepd. a series of alternative chelator-peptide conjugates labeled with 64Cu, measured in vitro receptor binding affinities in human breast cancer T47D cells expressing the gastrin-releasing peptide receptor (GRPR) and compared their in vivo stability in mice. DOTA-, NOTA-(1,4,7-triazacyclononane-1,4,7-triacetic acid), PCTA-(3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid), and Oxo-DO3A-(1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid) peptide conjugates were prepd. using H2N-Aoc-[D-Tyr6,βAla11,Thi13,Nle14]bombesin(6-14) (BBN) as a peptide template. The BBN moiety was selected since it binds with high affinity to the GRPR, which is overexpressed on human breast cancer cells. A convenient synthetic approach for the attachment of aniline-BFC to peptides on solid support is also presented. To facilitate the attachment of the aniline-PCTA and aniline-Oxo-DO3A to the peptide via an amide bond, a succinyl spacer was introduced at the N-terminus of BBN. The partially protected aniline-BFC (p-H2N-Bn-PCTA(Ot-Bu)3 or p-H2N-Bn-DO3A(Ot-Bu)3) was then coupled to the resulting N-terminal carboxylic acid preactivated with DEPBT/ClHOBt on resin. After cleavage and purifn., the peptide-conjugates were labeled with 64Cu using [64Cu]Cu(OAc)2 in 0.1 M ammonium acetate buffer at 100 °C for 15 min. Labeling efficacy was >90% for all peptides; Oxo-DO3A-BBN was incubated an addnl. 150 min at 100 °C to achieve this high yield. Specific activities varied from 76 to 101 TBq/mmol. Competition assays on T47D cells showed that all BFC-BBN complexes retained high affinity for the GRPR. All BFC-BBN 64Cu-conjugates were stable for over 20 h when incubated at 37 °C in mouse plasma samples. However, in vivo, only 37% of the 64Cu/Oxo-DO3A complex remained intact after 20 h while the 64Cu/DOTA-BBN complex was completely demetalated. In contrast, both 64Cu/NOTA- and 64Cu/PCTA-BBN conjugates remained stable during the 20 h time period. Our results indicate that it is possible to successfully conjugate aniline-BFC with peptide on solid support. Our data also show that 64Cu-labeled NOTA- and PCTA-BBN peptide conjugates are promising radiotracers for PET imaging of many human cancers overexpressing the GRP receptor.
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    59. 59
      Ferreira, C. L.; Lamsa, E.; Woods, M.; Duan, Y.; Fernando, P.; Bensimon, C.; Kordos, M.; Guenther, K.; Jurek, P.; Kiefer, G. E. Evaluation of Bifunctional Chelates for the Development of Gallium-Based Radiopharmaceuticals Bioconjugate Chem. 2010, 21, 531– 536
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      Evaluation of Bifunctional Chelates for the Development of Gallium-Based Radiopharmaceuticals
      Ferreira, Cara L.; Lamsa, Eric; Woods, Michael; Duan, Yin; Fernando, Pasan; Bensimon, Corinne; Kordos, Myra; Guenther, Katharina; Jurek, Paul; Kiefer, Garry E.
      Bioconjugate Chemistry (2010), 21 (3), 531-536CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      Ga radioisotopes, including the generator-produced positron-emitting isotope 68Ga (t1/2 = 68 min), are of increasing interest for the development of new radiopharmaceuticals. Bifunctional chelates (BFCs) that can be efficiently radiolabeled with Ga to yield complexes with good in vivo stability are needed. To this end, we undertook a systematic comparison of four BFCs contg. different chelating moieties: two novel BFCs, p-NO2-Bn-Oxo (1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid) and p-NO2-Bn-PCTA (3,6,9,15-tetraazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid), and two more commonly used BFCs, p-NO2-Bn-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and p-NO2-Bn-NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid). Each BFC was compared with respect to radiolabeling conditions, radiochem. yield, stability, and in vivo clearance properties. p-NO2-Bn-PCTA, p-NO2-Bn-Oxo, and p-NO2-Bn-NOTA were all more efficiently radiolabeled with Ga compared to p-NO2-Bn-DOTA. p-NO2-Bn-DOTA required longer reaction time, higher concns. of BFC, or heating to obtain equiv. radiochem. yields. Better stability was obsd. for p-NO2-Bn-NOTA and p-NO2-Bn-PCTA compared to p-NO2-Bn-DOTA and p-NO2-Bn-Oxo, esp. with respect to transmetalation to transferrin. Ga-radiolabled p-NO2-Bn-Oxo was found to be kinetically labile and therefore unstable in vivo. Ga-radiolabeled p-NO2-Bn-NOTA and p-NO2-Bn-PCTA were relatively inert, while Ga-radiolabeled p-NO2-Bn-DOTA had intermediate stability, losing >20% of Ga in less than one hour when incubated with apo-transferrin. Similar stability differences were seen when incubating at pH 2. In vivo PET imaging and biodistribution studies in mice showed that 68Ga-radiolabeled p-NO2-Bn-PCTA, p-NO2-Bn-NOTA, and p-NO2-Bn-DOTA all cleared through the kidneys. While there was no statistical difference in the biodistribution results of 68Ga-radiolabeled p-NO2-Bn-PCTA and p-NO2-Bn-DOTA, 68Ga-radiolabeled p-NO2-Bn-NOTA cleared more rapidly from blood and muscle tissue but retained at up to 5 times higher activity in the kidneys.
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    60. 60
      Ferreira, C. L.; Yapp, D. T.; Lamsa, E.; Gleave, M.; Bensimon, C.; Jurek, P.; Kiefer, G. E. Evaluation of novel bifunctional chelates for the development of Cu-64-based radiopharmaceuticals Nucl. Med. Biol. 2008, 35, 875– 882
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      Evaluation of novel bifunctional chelates for the development of Cu-64-based radiopharmaceuticals
      Ferreira, Cara L.; Yapp, Donald T.; Lamsa, Eric; Gleave, Martin; Bensimon, Corinne; Jurek, Paul; Kiefer, Garry E.
      Nuclear Medicine and Biology (2008), 35 (8), 875-882CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)
      Background: Currently available bifunctional chelates (BFCs) for attaching Cu-64 to a targeting mol. are limited by either their radiolabeling conditions or in vivo stability. With the goal of identifying highly effective BFCs, we compared the properties of two novel BFCs, 1-oxa-4,7,10-triazacyclododecane-S-5-(4-nitrobenzyl)-4,7,10-triacetic acid (p-NO2-Bn-Oxo) and 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-S-4-(4-nitrobenzyl)-3,6,9-triacetic acid (p-NO2-Bn-PCTA), with the commonly used S-2-(4-nitrobenzyl)-1,4,7,10-tetraazacyclododecanetetraacetic acid (p-NO2-Bn-DOTA). Methods: p-NO2-Bn-DOTA, p-NO2-Bn-Oxo and p-NO2-Bn-PCTA were each radiolabeled with Cu-64 under various conditions to assess the reaction kinetics and robustness of the radiolabeling. Stability of each Cu-64 BFC complex was evaluated at low pH and in serum. Small animal positron emission tomog. imaging and biodistribution studies in mice were undertaken. Results: p-NO2-Bn-Oxo and p-NO2-Bn-PCTA possessed superior reaction kinetics compared to p-NO2-Bn-DOTA under all radiolabeling conditions; >98% radiochem. yields were achieved in <5 min at room temp. even when using near stoichiometric amts. of BFC. Under nonideal conditions, such as low or high pH, high radiochem. yields were still achievable with the novel BFCs. The radiolabeled compds. were stable in serum and at pH 2 for 48 h. The imaging and biodistribution of the Cu-64-radiolabeled BFCs illustrated differences between the BFCs, including preferential clearance via the kidneys for the p-NO2-Bn-PCTA Cu-64 complex. Conclusions: The novel BFCs facilitated efficient Cu-64 radiolabeling under mild conditions to produce stable complexes at potentially high specific activities. These BFCs may find wide utility in the development of Cu-64-based radiopharmaceuticals.
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    61. 61
      Olszewski, R. T.; Bukhari, N.; Zhou, J.; Kozikowski, A. P.; Wroblewski, J. T.; Shamimi-Noori, S.; Wroblewska, B.; Bzdega, T.; Vicini, S.; Barton, F. B.; Neale, J. H. NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR J. Neurochem. 2004, 89, 876– 885
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      NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR
      Olszewski, Rafal T.; Bukhari, Noreen; Zhou, Jia; Kozikowski, Alan P.; Wroblewski, Jarda T.; Shamimi-Noori, Susan; Wroblewska, Barbara; Bzdega, Tomasz; Vicini, Stefano; Barton, Franca B.; Neale, Joseph H.
      Journal of Neurochemistry (2004), 89 (4), 876-885CODEN: JONRA9; ISSN:0022-3042. (Blackwell Publishing Ltd.)
      Phencyclidine (PCP) administration elicits pos. and neg. symptoms that resemble those of schizophrenia and is widely accepted as a model for the study of this human disorder. Group II metabotropic glutamate receptor (mGluR) agonists have been reported to reduce the behavioral and neurochem. effects of PCP. The peptide neurotransmitter, N-acetylaspartylglutamate (NAAG), is a selective group II agonist. The authors synthesized and characterized a urea-based NAAG analog, ZJ43. This novel compd. is a potent inhibitor of enzymes, glutamate carboxypeptidase II (Ki = 0.8 nM) and III (Ki = 23 nM) that deactivate NAAG following synaptic release. ZJ43 (100 μM) does not directly interact with NMDA receptors or metabotropic glutamate receptors. Administration of ZJ43 significantly reduced PCP-induced motor activation, falling while walking, stereotypic circling behavior, and head movements. To test the hypothesis that this effect of ZJ43 was mediated by increasing the activation of mGluR3 via increased levels of extracellular NAAG, the group II mGluR selective antagonist LY341495 was co-administered with ZJ43 prior to PCP treatment. This antagonist completely reversed the effects of ZJ43. Addnl., LY341495 alone increased PCP-induced motor activity and head movements suggesting that normal levels of NAAG act to moderate the effect of PCP on motor activation via a group II mGluR. These data support the view that NAAG peptidase inhibitors may represent a new therapeutic approach to some of the components of schizophrenia that are modeled by PCP.
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    62. 62
      Silver, D. A.; Pellicer, I.; Fair, W. R.; Heston, W. D.; Cordon-Cardo, C. Prostate-specific membrane antigen expression in normal and malignant human tissues Clin. Cancer Res. 1997, 3, 81– 95
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      Prostate-specific membrane antigen expression in normal and malignant human tissues
      Silver D A; Pellicer I; Fair W R; Heston W D; Cordon-Cardo C
      Clinical cancer research : an official journal of the American Association for Cancer Research (1997), 3 (1), 81-5 ISSN:1078-0432.
      Prostate-specific membrane antigen is a type II membrane protein with folate hydrolase activity produced by prostatic epithelium. The expression of this molecule has also been documented in extraprostatic tissues, including small bowel and brain. In the present study, an extensive immunohistochemical analysis was performed on a panel of well-characterized normal and malignant human tissues to further define the pattern of prostate-specific membrane antigen (PSMA) expression. Detectable PSMA levels were identified in prostatic epithelium, duodenal mucosa, and a subset of proximal renal tubules. A subpopulation of neuroendocrine cells in the colonic crypts also exhibited PSMA immunoreactivity. All other normal tissues, including cerebral cortex and cerebellum, had undetectable levels of PSMA. Thirty-three of 35 primary prostate adenocarcinomas and 7 of 8 lymph node metastases displayed tumor cell PSMA immunostaining. Eight of 18 prostate tumors metastatic to bone expressed PSMA. All of the other nonprostatic primary tumors studied had undetectable PSMA levels. However, intense staining was observed in endothelial cells of capillary vessels in peritumoral and endotumoral areas of certain malignancies, including 8 of 17 renal cell carcinomas, 7 of 13 transitional cell carcinomas, and 3 of 19 colon carcinomas. Extraprostatic PSMA expression appears to be highly restricted. Nevertheless, its diverse anatomical distribution implies a broader functional significance than previously suspected. The decrease in PSMA immunoreactivity noted in advanced prostate cancer suggests that expression of this molecule may be linked to the degree of tumor differentiation. The neoexpression of PSMA in endothelial cells of capillary beds in certain tumors may be related to tumor angiogenesis and suggests a potential mechanism for specific targeting of tumor neovasculature.
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    63. 63
      Prasanphanich, A. F.; Nanda, P. K.; Rold, T. L.; Ma, L.; Lewis, M. R.; Garrison, J. C.; Hoffman, T. J.; Sieckman, G. L.; Figueroa, S. D.; Smith, C. J. [64Cu-NOTA-8-Aoc-BBN(7–14)NH2] targeting vector for positron-emission tomography imaging of gastrin-releasing peptide receptor-expressing tissues Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 12462– 12467
      Google Scholar
      There is no corresponding record for this reference.
    64. 64
      Chen, Y.; Pullambhatla, M.; Foss, C. A.; Byun, Y.; Nimmagadda, S.; Senthamizhchelvan, S.; Sgouros, G.; Mease, R. C.; Pomper, M. G. 2-(3-{1-Carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pen tanedioic acid, [18F]DCFPyL, a PSMA-based PET imaging agent for prostate cancer Clin. Cancer Res. 2011, 17, 7645– 7653
      Google Scholar
      64
      2-(3-{1-Carboxy-5-[(6-[18F]Fluoro-Pyridine-3-Carbonyl)-Amino]-Pentyl}-Ureido)-Pentanedioic Acid, [18F]DCFPyL, a PSMA-Based PET Imaging Agent for Prostate Cancer
      Chen, Ying; Pullambhatla, Mrudula; Foss, Catherine A.; Byun, Youngjoo; Nimmagadda, Sridhar; Senthamizhchelvan, Srinivasan; Sgouros, George; Mease, Ronnie C.; Pomper, Martin G.
      Clinical Cancer Research (2011), 17 (24), 7645-7653CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
      PURPOSE: We have synthesized and evaluated in vivo 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid, [18F]DCFPyL, as a potential imaging agent for the prostate-specific membrane antigen (PSMA). PSMA is upregulated in prostate cancer epithelia and in the neovasculature of most solid tumors. Exptl. Design: [18F]DCFPyL was synthesized in two steps from the p-methoxybenzyl (PMB) protected lys-C(O)-glu urea precursor using 6-[18F]fluoronicotinic acid tetrafluorophenyl ester ([18F]F-Py-TFP) for introduction of 18F. Radiochem. synthesis was followed by biodistribution and imaging with PET in immunocompromised mice using isogenic PSMA PC3 PIP and PSMA- PC3 flu xenograft models. Human radiation dosimetry ests. were calcd. using OLINDA/EXM 1.0. RESULTS: DCFPyL displays a Ki value of 1.1 ± 0.1 nmol/L for PSMA. [18F]DCFPyL was produced in radiochem. yields of 36%-53% (decay cor.) and specific radioactivities of 340-480 Ci/mmol (12.6-17.8 GBq/μmol, n = 3). In an immunocompromised mouse model [18F]DCFPyL clearly delineated PSMA+ PC3 PIP prostate tumor xenografts on imaging with PET. At 2 h postinjection, 39.4 ± 5.4 percent injected dose per g of tissue (%ID/g) was evident within the PSMA+ PC3 PIP tumor, with a ratio of 358:1 of uptake within PSMA+ PC3 PIP to PSMA- PC3 flu tumor placed in the opposite flank. At or after 1 h postinjection, minimal nontarget tissue uptake of [18F]DCFPyL was obsd. The bladder wall is the dose-limiting organ. CONCLUSIONS: These data suggest [18F]DCFPyL as a viable, new positron-emitting imaging agent for PSMA-expressing tissues. Clin Cancer Res; 17(24); 7645-53.
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    65. 65
      Hillier, S. M.; Maresca, K. P.; Lu, G.; Merkin, R. D.; Marquis, J. C.; Zimmerman, C. N.; Eckelman, W. C.; Joyal, J. L.; Babich, J. W. 99mTc-Labeled Small-Molecule Inhibitors of Prostate-Specific Membrane Antigen for Molecular Imaging of Prostate Cancer J. Nucl. Med. 2013, 54, 1369– 1376
      Google Scholar
      There is no corresponding record for this reference.
    66. 66
      Elsasser-Beile, U.; Reischl, G.; Wiehr, S.; Buhler, P.; Wolf, P.; Alt, K.; Shively, J.; Judenhofer, M. S.; Machulla, H. J.; Pichler, B. J. PET imaging of prostate cancer xenografts with a highly specific antibody against the prostate-specific membrane antigen J. Nucl. Med. 2009, 50, 606– 611
      Google Scholar
      66
      PET imaging of prostate cancer xenografts with a highly specific antibody against the prostate-specific membrane antigen
      Elsasser-Beile Ursula; Reischl Gerald; Wiehr Stefan; Buhler Patrick; Wolf Philipp; Alt Karen; Shively John; Judenhofer Martin S; Machulla Hans-Jurgen; Pichler Bernd J
      Journal of nuclear medicine : official publication, Society of Nuclear Medicine (2009), 50 (4), 606-11 ISSN:0161-5505.
      UNLABELLED: Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, is highly expressed by virtually all prostate cancers and is currently the focus of several diagnostic and therapeutic strategies. We have previously reported on the generation of several monoclonal antibodies (mAb) and antibody fragments that recognize and bind with high affinity to the extracellular domain of cell-adherent PSMA. This article reports the in vivo behavior and tumor uptake of the radiolabeled anti-PSMA mAb 3/A12 and its potential as a tracer for PET. METHODS: The mAb 3/A12 was conjugated with the chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) and radiolabeled with (64)Cu. Severe combined immunodeficient mice bearing PSMA-positive C4-2 prostate carcinoma xenografts were used for small-animal PET imaging. Mice with PSMA-negative DU 145 tumors served as controls. For PET studies, each animal received 20-30 microg of radiolabeled mAb corresponding to an activity of 7.6-11.5 MBq. Imaging was performed 3, 24, and 48 h after injection. After the last scan, the mice were sacrificed and tracer in vivo biodistribution was measured by gamma-counting. RESULTS: Binding of the mAb 3/A12 on PSMA-expressing C4-2 cells was only minimally influenced by DOTA conjugation. The labeling efficiency using (64)Cu and DOTA-3/A12 was 95.3% +/- 0.3%. The specific activity after (64)Cu labeling was between 327 and 567 MBq/mg. After tracer injection, static small-animal PET images of mice with PSMA-positive tumors revealed a tumor-to-background ratio of 3.3 +/- 1.3 at 3 h, 7.8 +/- 1.4 at 24 h, and 9.6 +/- 2.7 at 48 h. In contrast, no significant tracer uptake occurred in the PSMA-negative DU 145 tumors. These results were confirmed by direct counting of tissues after the final imaging. CONCLUSION: Because of the high and specific uptake of (64)Cu-labeled mAb 3/A12 in PSMA-positive tumors, this ligand represents an excellent candidate for prostate cancer imaging and potentially for radioimmunotherapy.
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    67. 67
      Alt, K.; Wiehr, S.; Ehrlichmann, W.; Reischl, G.; Wolf, P.; Pichler, B. J.; Elsasser-Beile, U.; Buhler, P. High-resolution animal PET imaging of prostate cancer xenografts with three different 64Cu-labeled antibodies against native cell-adherent PSMA Prostate 2010, 70, 1413– 1421
      Google Scholar
      There is no corresponding record for this reference.
    68. 68
      Fischer, G.; Seibold, U.; Schirrmacher, R.; Wangler, B.; Wangler, C. (89)Zr, a radiometal nuclide with high potential for molecular imaging with PET: chemistry, applications and remaining challenges Molecules 2013, 18, 6469– 6490
      Google Scholar
      There is no corresponding record for this reference.
    69. 69
      Cheng, Y.; Prusoff, W. H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50% inhibition (I50) of an enzymatic reaction Biochem. Pharmacol. 1973, 22, 3099– 3108
      Google Scholar
      69
      Relation between the inhibition constant K1) and the concentration of inhibitor which causes fifty per cent inhibition (I50) of an enzymic reaction
      Cheng, Yung-Chi; Prusoff, William H.
      Biochemical Pharmacology (1973), 22 (23), 3099-108CODEN: BCPCA6; ISSN:0006-2952.
      The Ki and I50 values are equal where the kinetics are non- or uncompetitive, but not where they are competitive. The relation between the 2 values was analyzed for non- and uncompetitive bi- and monosubstrate reactions and for competitive bisubstrate reactions.
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