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18F-Based Pretargeted PET Imaging Based on Bioorthogonal Diels–Alder Click Chemistry

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† Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States
‡ MabVax Therapeutics, 11588 Sorrento Valley Road Suite 20, San Diego, California 92121, United States
§ Department of Chemistry, Hunter College of the City University of New York, 695 Park Avenue, New York, New York 10065, United States
∥ The Graduate Center, City University of New York, 365 Fifth Avenue, New York, New York 10016, United States
⊥ Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States
*E-mail: [email protected]
*E-mail: [email protected]
Cite this: Bioconjugate Chem. 2016, 27, 2, 298–301
Publication Date (Web):October 19, 2015
https://doi.org/10.1021/acs.bioconjchem.5b00504

Copyright © 2015 American Chemical Society. This publication is licensed under these Terms of Use.

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Abstract

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A first-of-its-kind 18F pretargeted PET imaging approach based on the bioorthogonal inverse electron demand Diels–Alder (IEDDA) reaction between tetrazine (Tz) and trans-cyclooctene (TCO) is presented. As proof-of-principle, a TCO-bearing immunoconjugate of the anti-CA19.9 antibody 5B1 and an Al[18F]NOTA-labeled tetrazine radioligand were harnessed for the visualization of CA19.9-expressing BxPC3 pancreatic cancer xenografts. Biodistribution and 18F-PET imaging data clearly demonstrate that this methodology effectively delineates tumor mass with activity concentrations up to 6.4 %ID/g at 4 h after injection of the radioligand.

SPECIAL ISSUE

This article is part of the Molecular Imaging Probe Chemistry special issue.

Over the past two decades, pretargeting strategies linking antibody targeting vectors and small molecule radioligands have emerged as powerful tools for the in vivo positron emission tomography (PET) of cancer. (1) These methods effectively leverage the principal advantages of both species while skirting their inherent limitations. (2) Despite their slow pharmacokinetics, antibodies possess remarkable specificity and affinity for tumor biomarkers, and thus immunoconjugates bearing click chemistry moieties can provide excellent targeted platforms for in vivo bioorthogonal reactions. (3) In most pretargeting methodologies, the in vivo hapten is a radiolabeled small molecule with rapid pharmacokinetics. Without question, the most important facet of pretargeting strategies is the ability to radiolabel the antibody after it has reached the tumor, a trait which facilitates the use of short-lived radioisotopes that would normally be incompatible with the multiday biological half-lives of IgG vectors. This, in turn, dramatically reduces the radiation doses to healthy tissues compared to traditional radioimmunoconjugates directly labeled with long-lived radioisotopes such as 124I (t1/2 = 4.2 d) or 89Zr (t1/2 = 3.2 d). (4)

The IEDDA reaction between a 1,2,4,5-tetrazine (Tz) and a trans-cyclooctene (TCO) is one of the most rapid bioorthogonal click ligations and, as such, is remarkably well suited for pretargeting strategies. (5-9) Indeed, pretargeted imaging based on the IEDDA reaction has already been proven to be feasible in vivo. (3, 6-10) For example, the human A33 (huA33) antibody and a 64Cu-labeled radioligand have recently been successfully employed for the pretargeted PET imaging of SW1222 human colorectal cancer xenografts. (3, 11) In this case, it was shown that the pretargeted approach visualized the malignant tissue with comparable tumor-to-background contrast at only a fraction of the off-target radiation dose to healthy tissue, when compared to traditional radioimmunoconjugation approaches.

With this in mind, it follows that the creation of a pretargeting strategy featuring an even shorter-lived radionuclide such as 18F (t1/2 = 109.8 min) is the next logical step, as this could exploit the dosimetric advantages of pretargeting even further. The aluminum-[18F]fluoride-NOTA-complex (12-14) (Al[18F]-NOTA) has previously been shown to be a stable and synthetically efficient methodology for the radiolabeling of both biomolecules (15, 16) and small molecules (17) with [18F]fluoride. Considering the well-documented instability of tetrazines under the alkaline conditions required for nucleophilic 18F-fluorination reactions, the Al[18F]-NOTA approach seems to be particularly appropriate for the synthesis of 18F-labeled tetrazine radioligands. (18-20) Despite known procedures for the radiosynthesis of 18F-labeled TCO, (21, 22) we chose to apply the Al[18F]-NOTA-approach to tetrazines in order to be able to use readily available TCO-modified 5B1 for in vivo pretargeting of CA19.9.

Herein, we report the development of a novel Tz/TCO-based pretargeting strategy using an Al[18F]-NOTA-labeled tetrazine radioligand. For our proof-of-concept system, we selected the 5B1 antibody, a fully human IgG that targets a promising biomarker for pancreatic ductal adenocarcinoma: carbohydrate antigen 19.9 (CA19.9). (23, 24) In order to arm the antibody with the reactive bioorthogonal moiety, purified 5B1 was incubated with an activated succinimidyl ester of TCO (TCO-NHS, 35 equiv.) at room temperature for 1 h. The immunoconjugate was subsequently purified by gel-filtration chromatography. The precursor to the radioligand, Tz-PEG11-NOTA (1, Scheme 1), was synthesized from three commercially available building blocks: 2,5-dioxo-1-pyrrolidinyl 5-[4-(1,2,4,5-tetrazin-3-yl)benzylamino]-5-oxopentanoate (Tz-NHS), O-(2-aminoethyl)-O′-[2-(boc-amino)ethyl]decaethylene glycol (NH2-PEG11-NHBoc), and S-2-(4-isothiocyanatobenzyl)-1,4,7-triaza-cyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA). After the peptide coupling between Tz-NHS and NH2-PEG11-NHBoc and the subsequent deprotection of the terminal tert-butyloxycarbonyl protecting group, the resulting Tz-PEG11-NH2 moiety was reacted with the bifunctional p-SCN-Bn-NOTA chelator. Ultimately, the precursor was prepared in very high purity (>98%) and with an overall yield of ∼15% (n = 3).

The 18F-labeled radioligand Tz-PEG11-Al[18F]-NOTA ([18F]2) was obtained in 54–65% radiochemical yield [decay-corrected (d.c.) to the start of synthesis] in high purity (>96%) and a specific activity between 21.4 and 26.7 GBq/μmol (for more detailed experimental data, see Supporting Information). The use of metal-free solvents, the pH of the Al[18F]-NOTA complexation reaction (pH = 4), and the ratio of reaction solvents (at least 3:1 MeCN/H2O) all proved to be crucial factors in obtaining high radiochemical yields. The in vitro stability of [18F]2 was assayed by incubation in phosphate buffered saline (PBS, pH 7.4) or human serum at 37 °C, followed by analysis via radio-HPLC. In PBS, negligible decomposition could be observed after 4 h (92 ± 2.3% intact), and 79 ± 4.4% (n = 4) of the radioligand remained intact in human serum at the same time point. The in vivo stability was determined by injecting [18F]2 (150 μCi in 150 μL 0.9% sterile saline) into healthy athymic nude mice. Blood was subsequently collected via cardiac puncture and 63 ± 8.9% (n = 3) of the radioligand was found intact 4 h after injection. Given the fast reaction kinetics of the IEDDA ligation as well as the relatively short half-life of 18F, the observed degradation rate is not considered a detriment to the system, as shown for other Tz/TCO approaches. (3, 19)

Scheme 1

Scheme 1. Radiochemical Synthesis of the Radioligand Tz-PEG11-Al[18F]-NOTA ([18F]2)a
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Scheme a[18F]2 was obtained in 54–56% RCY (d.c.) and high SAs (21.4–26.7 GBq/μmol) after a total synthesis time of 108 min. Purification of the crude reaction mixture using a C18-cartridge gave [18F]2 in purities >96%.

The bioorthogonal click reaction between [18F]2 and the TCO moiety on the antibody was demonstrated by incubation of equimolar amounts (1.33 nmol) of the purified radioligand with 5B1-TCO at room temperature. Analysis of the reaction via radio-TLC (mobile phase: 90% MeCN in H2O) revealed a > 94% yield for the reaction measured by the consumption of [18F]2, with the 18F-labeled click reaction product situated at the origin, while the free radioligand can be detected at the solvent front (see Supporting Information). In all experiments throughout this study, the equimolar amount of tetrazine is calculated relative to the antibody 5B1 (and not the TCO).

Ex vivo biodistribution data for Tz-PEG11-Al[18F]-NOTA were first obtained in healthy mice by injecting [18F]2 alone (1.8–2.0 MBq) via the tail vein (Figure 1). The data shows accumulation and retention of the radiotracer in the large intestines and feces with 0.32 ± 0.87% injected dose per gram (%ID/g) at 1 h after injection to 1.73 ± 0.45 %ID/g at 4 h. The uptake and retention of [18F]2 could also be observed in the kidneys (2.12 ± 0.23 %ID/g at 1 h to 1.17 ± 0.12% ID/g at 4 h), indicating dual renal and fecal elimination pathways for the radioligand. The amount of activity in the blood decreases over time, from 1.94 ± 0.23 %ID/g at 1 h to 0.78 ± 0.08 %ID/g at 4 h after injection, while the uptake in all other healthy tissues remained <1 %ID/g. Critically, the activity concentrations in the bone were particularly low (≤0.2 %ID/g), illustrating the high in vivo stability of the Al[18F]-NOTA complex. In accompanying experiments, the blood half-life of the radioligand was calculated to be 71.2 ± 5.4 min.

Figure 1

Figure 1. Biodistribution of the radioligand [18F]2 in healthy athymic nude mice. The 18F-labeled tracer (1.33 nmol, 1.8–2.0 MBq) was injected via the tail vein before the mice were euthanized, and the organs collected at the appropriate time points.

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In subsequent pretargeted biodistribution experiments, nude, athymic mice bearing subcutaneous CA19.9-expressing BxPC3 xenografts were injected with 5B1-TCO (1.33 nmol of 5B1) 72 h prior to the administration of [18F]2 (1.33 nmol, 1.8–2.0 MBq) (Figure 2).

Figure 2

Figure 2. Results of the biodistribution pretargeting CA19.9 with [18F]2/5B1-TCO. Subcutaneous BxPC3 xenograft bearing mice were administered 5B1-TCO (1.33 nmol) 72 h prior to the injection of the 18F-labeled tracer (1.33 nmol, 1.8–2.0 MBq) via the tail vein before the mice were euthanized, and the organs collected at the appropriate time points.

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The data revealed increasing tumoral uptake over the course of the study (3.0 ± 0.32 %ID/g at 30 min, 3.52 ± 0.67 %ID/g at 1 h, 4.81 ± 1.23 %ID/g at 2 h to 5.6 ± 0.85 %ID/g at 4 h), with the amount of radioactivity in the blood decreasing in kind, from 6.13 ± 0.86 %ID/g at 30 min to 1.75 ± 0.22 %ID/g at 4 h. In accordance with the biodistribution data obtained from healthy mice, the uptake in other tissue remained generally low (≤2 %ID/g), with the highest uptake and retention in the clearance organs: the intestines and kidneys. The clearance of radioactivity from the blood pool was generally in line with the calculated blood half-life of the radiotracer, and the steady uptake of radioactivity at the tumor suggested that the radioligand is primarily clicking with 5B1-TCO at the tumor site rather than clicking in the blood pool followed by accumulation at the tumor.

Pretargeted small animal PET imaging experiments were conducted in a similar fashion, with the only difference in the amount of radioactivity injected (18–20 MBq, 1.33 nmol of [18F]2, equimolar to 5B1-TCO) (Figure 3).

Figure 3

Figure 3. PET images of Tz-PEG11-Al[18F]-NOTA/5B1-TCO pretargeting strategy. Subcutaneous BxPC3 xenograft bearing mice were administered 5B1-TCO (1.33 nmol) 72 h prior to the injection of the 18F-labeled tracer (1.33 nmol, 18–20 MBq) via the tail vein. Transverse (top) and coronal (middle) planar images intersect the center of the tumors. The maximum intensity projections (MIPs, bottom) clearly illustrate tumor uptake after 1 h with increasing tumor-to-background ratios over the course of the experiment.

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The PET images confirm the data obtained in the biodistribution study: the signal in the tumor increases with time, while the activity concentrations in the blood and intestines concomitantly decrease. This results in the clear delineation of the tumor from background tissue, with the tumor-to-background activity ratios improving over the course of the experiment. The tumoral uptake of [18F]2 is immediately evident 1 h after injection; however, the signal grows to 6.4 %ID/g at 4 h after the administration of the radioligand. Admittedly, while the tumor-to-background activity concentration ratios improve over time, the radioactivity has not cleared the intestines at 4 h postinjection. Considering the blood half-life (71.2 ± 5.4 min) of the radioligand and the observed increasing tumor uptake over the course of the experiment, it seems reasonable and interesting to include a later imaging and biodistribution time point (e.g., 6 h p.i.) in future experiments in order to evaluate whether an improved tumor-to-background ratio can be observed at later time points. In terms of control conditions, previous studies in our laboratory have shown that no tumor uptake could be observed when IgG-TCO instead of 5B1-TCO was injected into BxPC3-bearing mice, suggesting that the observed tumor uptake is a result of in vivo click reactions occurring at the tumor site. (3, 25)

In light of these results, second generation tetrazine-bearing radioligands are currently in development in our laboratory in an effort to determine whether structural alterations can increase the fraction of the radioligand that is excreted via the renal system and thus create higher tumor-to-background ratios at earlier time points. Finally, using the biodistribution data, we performed a dosimetric analysis of the pretargeting strategy that confirms that pretargeted PET imaging with Tz-PEG11-Al[18F]-NOTA and 5B1-TCO confers a significant dosimetric advantage over the use of antibodies directly labeled with long-lived radioisotopes (in this case 89Zr-DFO-5B1). The effective dose of the presented 18F-based pretargeting system (0.03 rem/mCi) is more than 60 times lower than directly labeled 89Zr-DFO-5B1 (2.02 rem/mCi; see Supporting Information).

In sum, this novel 18F-based pretargeted PET imaging system shows highly promising biodistribution results and produced tumoral activity concentrations of up to 6.4 %ID/g at 4 h postinjection. Small-animal PET imaging experiments revealed that this methodology clearly delineates CA19.9-expressing tissues with especially enticing tumor-to-background activity ratios 2 and 4 h after injection of the radiotracer.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.bioconjchem.5b00504.

  • Synthesis of the precursor 1, dosimetry calculations, and experimental details (PDF)

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  • Corresponding Authors
    • Brian M. Zeglis - Department of Chemistry, Hunter College of the City University of New York, 695 Park Avenue, New York, New York 10065, United States;  The Graduate Center, City University of New York, 365 Fifth Avenue, New York, New York 10016, United States;  Email: [email protected]
    • Jason S. Lewis - Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States;  Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States;  Email: [email protected]
  • Authors
    • Jan-Philip Meyer - Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States
    • Jacob L. Houghton - Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States
    • Paul Kozlowski - Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States
    • Dalya Abdel-Atti - Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States
    • Thomas Reiner - Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States
    • Naga Vara Kishore Pillarsetty - Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, United States
    • Wolfgang W. Scholz - MabVax Therapeutics, 11588 Sorrento Valley Road Suite 20, San Diego, California 92121, United States
  • Notes
    The authors declare the following competing financial interest(s): Wolfgang W. Scholz is an employee of MabVax Therapeutics and has an equity interest.

Acknowledgment

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The authors gratefully acknowledge the MSKCC Small Animal Imaging Core Facility as well as the Radiochemistry and Molecular Imaging Probe core, which were supported in part by NIH grant P30 CA08748. The authors also would like to thank the NIH (K25 EB016673, T.R.; F32 CA180452 and R25CA096945, J.L.H.; 4R00 CA178205-2, B.M.Z.; 2R42CA128362, MabVax). We also gratefully acknowledge Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Center for Experimental Therapeutics of Memorial Sloan Kettering Cancer Center.

References

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  8. 8
    Emmetiere, F., Irwin, C., Viola-Villegas, N. T., Longo, V., Cheal, S. M., Zanzonico, P., Pillarsetty, N., Weber, W. A., Lewis, J. S., and Reiner, T. (2013) 18F-Labeled-Bioorthogonal Liposomes for In Vivo Targeting Bioconjugate Chem. 24, 1784– 89 DOI: 10.1021/bc400322h
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    8
    18F-Labeled-Bioorthogonal Liposomes for In Vivo Targeting
    Emmetiere, Fabien; Irwin, Christopher; Viola-Villegas, Nerissa Therese; Longo, Valerie; Cheal, Sarah M.; Zanzonico, Pat; Pillarsetty, NagaVaraKishore; Weber, Wolfgang A.; Lewis, Jason S.; Reiner, Thomas
    Bioconjugate Chemistry (2013), 24 (11), 1784-1789CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    Liposomes are attractive vehicles for the controlled release of drugs and cytotoxins and have a long-standing history in medical research and clin. practice. In addn. to established therapeutic indications, liposomes have several favorable properties for mol. imaging, including high stability and the ability to be labeled with radioisotopes, as well as paramagnetic and fluorescent contrast agents. However, long circulation times and difficulties in creating targeted liposomes have proven challenges for imaging. In this study, we have addressed these limitations using a recently developed strategy for bioorthogonal conjugation, the reaction between tetrazines and trans-cyclooctenes. By coating radiolabeled liposomes with trans-cyclooctene and pretargeting with a tetrazine coupled to a targeted peptide, we were able to selectively enhance the retention of liposomes and bind them to tumor tissue in live animals. The rapid reaction between tetrazines and trans-cyclooctenes allowed imaging to be performed with the short-lived PET tracer 18F, yielding signal-to-background activity ratios of 7:1. The covalent, bioorthogonally driven tumor-targeting of liposomes by in vivo click chem. is promising and should be explored for more selective and rapid delivery of radiodiagnostics and radiotherapeutics, two classes of drugs which particularly benefit from fast clearance, low nonspecific binding, and the assocd. reduced toxicity to kidneys and bone marrow.
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  9. 9
    Denk, C., Svatunek, D., Filip, T., Wanek, T., Lumpi, D., Froehlich, J., Kuntner, C., and Mikula, H. (2014) Development of a 18F-labeled tetrazine with favorable pharmacokinetics for bioorthogonal PET imaging Angew. Chem., Int. Ed. 53, 9655– 59 DOI: 10.1002/anie.201404277
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    9
    Development of a 18F-Labeled Tetrazine with Favorable Pharmacokinetics for Bioorthogonal PET Imaging
    Denk, Christoph; Svatunek, Dennis; Filip, Thomas; Wanek, Thomas; Lumpi, Daniel; Froehlich, Johannes; Kuntner, Claudia; Mikula, Hannes
    Angewandte Chemie, International Edition (2014), 53 (36), 9655-9659CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A low-mol.-wt. 18F-labeled tetrazine deriv. was developed as a highly versatile tool for bioorthogonal PET imaging. Prosthetic groups and undesired carrying of 18F through addnl. steps were evaded by direct 18F-fluorination of an appropriate tetrazine precursor. Reaction kinetics of the cycloaddn. with trans-cyclooctenes were investigated by applying quantum chem. calcns. and stopped-flow measurements in human plasma; the results indicated that the labeled tetrazine is suitable as a bioorthogonal probe for the imaging of dienophile-tagged (bio)mols. In vitro and in vivo investigations revealed high stability and PET/MRI in mice showed fast homogeneous biodistribution of the 18F-labeled tetrazine that also passes the blood-brain barrier. An in vivo click expt. confirmed the bioorthogonal behavior of this novel tetrazine probe. Due to favorable chem. and pharmacokinetic properties this bioorthogonal agent should find application in bioimaging and biomedical research.
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  10. 10
    Herth, M. M., Andersen, V. L., Lehel, S., Madsen, J., Knudsen, G. M., and Kristensen, J. L. (2013) Development of a 11C-labeled tetrazine for rapidtetrazine-trans-cyclooctene ligation Chem. Commun. 49, 3805– 7 DOI: 10.1039/c3cc41027g
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  11. 11
    Zeglis, B. Z., Brand, C., Abdel-Atti, D., Carnazza, K. E., Cook, B. E., Carlin, S., Reiner, T., and Lewis, J. S. (2015) Optimization of a Pretargeted Strategy for the PET Imaging of Colorectal Carcinoma via the Modulation of Radioligand Pharmacokinetics Mol. Pharmaceutics 12, 3575– 87 DOI: 10.1021/acs.molpharmaceut.5b00294
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    11
    Optimization of a Pretargeted Strategy for the PET Imaging of Colorectal Carcinoma via the Modulation of Radioligand Pharmacokinetics
    Zeglis, Brian M.; Brand, Christian; Abdel-Atti, Dalya; Carnazza, Kathryn E.; Cook, Brendon E.; Carlin, Sean; Reiner, Thomas; Lewis, Jason S.
    Molecular Pharmaceutics (2015), 12 (10), 3575-3587CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    Pretargeted PET imaging has emerged as an effective strategy for merging the exquisite selectivity of antibody-based targeting vectors with the rapid pharmacokinetics of radiolabeled small mols. We previously reported the development of a strategy for the pretargeted PET imaging of colorectal cancer based on the bioorthogonal inverse electron demand Diels-Alder reaction between a tetrazine-bearing radioligand and a transcyclooctene-modified huA33 immunoconjugate. Although this method effectively delineated tumor tissue, its clin. potential was limited by the somewhat sluggish clearance of the radioligand through the gastrointestinal tract. Herein, we report the development and in vivo validation of a pretargeted strategy for the PET imaging of colorectal carcinoma with dramatically improved pharmacokinetics. Two novel tetrazine constructs, Tz-PEG7-NOTA and Tz-SarAr, were synthesized, characterized, and radiolabeled with 64Cu in high yield (>90%) and radiochem. purity (>99%). PET imaging and biodistribution expts. in healthy mice revealed that although 64Cu-Tz-PEG7-NOTA is cleared via both the gastrointestinal and urinary tracts, 64Cu-Tz-SarAr is rapidly excreted by the renal system alone. On this basis, 64Cu-Tz-SarAr was selected for further in vivo evaluation. To this end, mice bearing A33 antigen-expressing SW1222 human colorectal carcinoma xenografts were administered huA33-TCO, and the immunoconjugate was given 24 h to accumulate at the tumor and clear from the blood, after which 64Cu-Tz-SarAr was administered via i.v. tail vein injection. PET imaging and biodistribution expts. revealed specific uptake of the radiotracer in the tumor at early time points (5.6 ± 0.7 %ID/g at 1 h p.i.), high tumor-to-background activity ratios, and rapid elimination of unclicked radioligand. Importantly, expts. with longer antibody accumulation intervals (48 and 120 h) yielded slight decreases in tumoral uptake but also concomitant increases in tumor-to-blood activity concn. ratios. This new strategy offers dosimetric benefits as well, yielding a total ED of 0.041 rem/mCi, far below the doses produced by directly labeled 64Cu-NOTA-huA33 (0.133 rem/mCi) and 89Zr-DFO-huA33 (1.54 rem/mCi). Ultimately, this pretargeted PET imaging strategy boasts a dramatically improved pharmacokinetic profile compared to our first generation system and is capable of clearly delineating tumor tissue with high image contrast at only a fraction of the radiation dose created by directly labeled radioimmunoconjugates.
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  12. 12
    McBride, W. J., D’Souza, C. A., Sharkey, R. M., Karacay, H., Chang, C., and Goldenberg, D. M. (2010) Improved 18F Labeling of Peptides with a Fluoride-Aluminum Chelate Complex Bioconjugate Chem. 21, 1331– 40 DOI: 10.1021/bc100137x
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    12
    Improved 18F Labeling of Peptides with a Fluoride-Aluminum-Chelate Complex
    McBride, William J.; D'Souza, Christopher A.; Sharkey, Robert M.; Karacay, Habibe; Rossi, Edmund A.; Chang, Chien-Hsing; Goldenberg, David M.
    Bioconjugate Chemistry (2010), 21 (7), 1331-1340CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    We reported previously the feasibility to radiolabel peptides with fluorine-18 (18F) using a rapid one-pot method that first mixes 18F- with Al3+ and then binds the (Al18F)2+ complex to a NOTA ligand on the peptide. We examd. several new NOTA ligands and detd. how temp., reaction time, and reagent concn. affected the radiolabeling yield. Four structural variations of the NOTA ligand had isolated radiolabeling yields ranging from 5.8% to 87% under similar reaction conditions. All of the Al18F NOTA complexes were stable in vitro in human serum, and those that were tested in vivo also were stable. The radiolabeling reactions were performed at 100°, and the peptides could be labeled in as little as 5 min. The IMP467 peptide could be labeled up to 115 GBq/μmol (3100 Ci/mmol), with a total reaction and purifn. time of 30 min without chromatog. purifn.
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  13. 13
    Richter, S. and Wuest, F. (2014) 18F-Labeled Peptides: The Future Is Bright Molecules 19, 20536– 56 DOI: 10.3390/molecules191220536
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    13
    18F-labeled peptides: the future is bright
    Richter, Susan; Wuest, Frank
    Molecules (2014), 19 (12), 20536-20556, 21 pp.CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    A review. Radiolabeled peptides have been the subject of intense research efforts for targeted diagnostic imaging and radiotherapy over the last 20 years. Peptides offer several advantages for receptor imaging and targeted radiotherapy. The low mol. wt. of peptides allows for rapid clearance from the blood and non-target tissue, which results in favorable target-to-non-target ratios. Moreover, peptides usually display good tissue penetration and they are generally non-immunogenic. A major drawback is their potential low metabolic stability. The majority of currently used radiolabeled peptides for targeted mol. imaging and therapy of cancer is labeled with various radiometals like 99mTc, 68Ga, and 177Lu. However, over the last decade an increasing no. of F-labeled peptides have been reported. Despite of obvious advantages of 18F like its ease of prodn. in large quantities at high specific activity, the low β+ energy (0.64 MeV) and the favorable half-life (109.8 min), 18F-labeling of peptides remains a special challenge. The first part of this review will provide a brief overview on chem. strategies for peptide labeling with 18F. A second part will discuss recent technol. advances for 18F-labeling of peptides with special focus on microfluidic technol., automation, and kit-like prepn. of 18F-labeled peptides.
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  14. 14
    Pan, D., Yan, Y., Yang, R., Xu, Y. P., Chen, F., Wang, L., Luo, S., and Yang, M. (2014) PET imaging of prostate tumors with 18F-Al-NOTA-MATBBN Contrast Media Mol. Imaging 9, 342– 8 DOI: 10.1002/cmmi.1583
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    14
    PET imaging of prostate tumors with 18F-Al-NOTA-MATBBN
    Pan, Donghui; Yan, Yongjun; Yang, Ronghua; Xu, Yu Ping; Chen, Fei; Wang, Lizhen; Luo, Shineng; Yang, Min
    Contrast Media & Molecular Imaging (2014), 9 (5), 342-348CODEN: CMMICO; ISSN:1555-4309. (Wiley-Blackwell)
    Overexpression of the gastrin-releasing peptide receptor (GRPR) in prostate cancer provides a promising target for detection the disease. MATBBN is a new bombesin analog originating from the GRPR antagonists with a hydrophilic linker. In this study NOTA-conjugated MATBBN was labeled by the Al18F method and the potential of 18F-Al-NOTA-MATBBN for prostate tumor PET imaging was also evaluated. NOTA-MATBBN was radiolabeled with 18F using Al18F complexes. Partition coeff., in vitro stability and GRPR binding affinity were also detd. PET studies were performed with 18F-Al-NOTA-MATBBN in PC-3 tumor-bearing mice. 18F-Al-NOTA-MATBBN can be produced within 30 min with a decay-cor. yield of 62.5 ± 2.1% and a radiochem. purity of >98%. The logP octanol-water value for the Al18F-labeled BBN analog was -2.40 ± 0.07 and the radiotracer was stable in phosphate-buffered saline and human serum for 2 h. The IC50 values of displacement for the 18F-Al-NOTA-MATBBN with MATBBN was 126.9 ± 2.75 nm. The PC-3 tumors were clearly visible with high contrast after injection of the labeled peptide. At 60 min post-injection, the tumor uptakes for 18F-Al-NOTA-MATBBN and 18F-FDG were 4.59 ± 0.43 and 1.98 ± 0.35% injected dose/g, and tumor to muscle uptake radios for two tracers were 6.77 ± 1.10 and 1.78 ± 0.32, resp. Dynamic PET revealed that 18F-Al-NOTA-MATBBN was excreted mainly through the kidneys. GRPR-binding specificity was also demonstrated by reduced tumor uptake of 18F-Al-NOTA-MATBBN after coinjection with excess unlabeled MATBBN peptide at 1 h post-injection. NOTA- MATBBN could be labeled rapidly with 18F using one step method. 18F-Al-NOTA-MATBBN may be a promising PET imaging agent for prostate cancer. Copyright © 2014 John Wiley & Sons, Ltd.
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  15. 15
    McBride, W. J., Sharkey, R. M., Karacay, H., D’Souza, C. A., Rossi, E. A., Laverman, P., Chang, C., Boerman, O. C., and Goldenberg, D. M. (2009) A novel method for 18F Radiolabeling for PET J. Nucl. Med. 50, 991– 8 DOI: 10.2967/jnumed.108.060418
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  16. 16
    McBride, W. J., D’Souza, C. A., Karacay, H., Sharkey, R. M., and Goldenberg, D. M. (2012) New Lyophilized Kit for Rapid Radiofluorination of Peptides Bioconjugate Chem. 23, 538– 47 DOI: 10.1021/bc200608e
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    16
    New Lyophilized Kit for Rapid Radiofluorination of Peptides
    McBride, William J.; D'Souza, Christopher A.; Karacay, Habibe; Sharkey, Robert M.; Goldenberg, David M.
    Bioconjugate Chemistry (2012), 23 (3), 538-547CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    Radiolabeling compds. with positron-emitting radionuclides often involves a time-consuming, customized process. Herein, we report a simple lyophilized kit formulation for labeling peptides with 18F, based on the aluminum-fluoride procedure. The prototype kit contains IMP485, a NODA (1,4,7-triazacyclononane-1,4-diacetate)-MPAA (Me phenylacetic acid)-di-HSG (histamine-succinyl-glycine) hapten-peptide, [NODA-MPAA-d-Lys(HSG)-d-Tyr-d-Lys(HSG)-NH2], used for pretargeting, but we also examd. a similar kit formulation for a somatostatin-binding peptide [IMP466, NOTA-d-Phe-Cys-Phe-d-Trp-Lys-Thr-Cys-Throl] bearing a NOTA ligand to det. if the benefits of using a kit can be extended to other AlF-binding peptides. The NODA-MPAA ligand forms a single stable complex with (AlF)2+ in high yields. In order to establish suitable conditions for a facile kit, the formulation was optimized for pH, peptide to Al3+ ratio, bulking agent, radioprotectant, and the buffer. For optimal labeling, the kit was reconstituted with an aq. soln. of 18F- and ethanol (1:1), heated at 100-110 °C for 15 min, and then simply and rapidly purified using one of two equally effective solid-phase extn. (SPE) methods. Al18F-IMP485 was isolated as a single isomer complex, in high yield (45-97%) and high specific activity (up to 223 GBq/μmol), within 20 min. The labeled product was stable in human serum at 37 °C for 4 h and in vivo, urine samples showed the intact product was eliminated. Tumor targeting of the Al18F-IMP485 in nude mice bearing human colon cancer xenografts pretargeted with an anti-CEACAM5 bispecific antibody showed very low uptake (0.06% ± 0.02 ID/g) in bone, further illustrating its stability. At 1 h, pretargeted animals had high Al18F-IMP485 tumor uptake (28.1% ± 4.5 ID/g), with ratios of 9 ± 4, 123 ± 38, 110 ± 43, and 120 ± 108 for kidney, liver, blood and bone, resp. Tumor uptake remained high at 3 h postinjection, with increased tumor/nontumor ratios. The NOTA-somatostatin-binding peptide also was fluorinated with good yield and high specific activity in the same kit formulation. However, yields were somewhat lower than those achieved with IMP485 contg. the NODA-MPAA ligand, likely reflecting this ligand's superior binding properties over the simple NOTA. These studies indicate that 18F-labeled peptides can be reproducibly prepd. as stable Al-F complexes with good radiochem. yield and high specific activity using a simple, one-step, lyophilized kit followed by a rapid purifn. by SPE that provides the 18F-peptide ready for patient injection within 30 min.
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  17. 17
    Hoigebazar, L., Jeong, J. M., Lee, J., Shetty, D., Yang, B. Y., Lee, Y., Lee, D. S., Chung, J., and Lee, M. C. (2012) Syntheses of 2-Nitroimidazole Derivatives Conjugated with 1,4,7-Tiazacyclononae-N,N′-Diacetic Acid Labeled with F-18 Using an Aluminum Complex Method for Hypoxia Imaging J. Med. Chem. 55, 3155– 62 DOI: 10.1021/jm201611a
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  18. 18
    Zeglis, B. M., Emmetiere, F., Pillarsetty, N., Weissleder, R., Lewis, J. S., and Reiner, T. (2014) Building Blocks for the Construction of Bioorthogonally Reactive Peptides via Solid Phase Peptide Synthesis ChemistryOpen 3, 48– 53 DOI: 10.1002/open.201402000
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  19. 19
    Karver, M. R., Weissleder, R., and Hilderbrand, S. A. (2011) Synthesis and evaluation of a series of 1,2,4,5-tetrazines for bioorthogonal conjugation Bioconjugate Chem. 22, 2263– 70 DOI: 10.1021/bc200295y
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    19
    Synthesis and evaluation of a series of 1,2,4,5-tetrazines for bioorthogonal conjugation
    Karver, Mark R.; Weissleder, Ralph; Hilderbrand, Scott A.
    Bioconjugate Chemistry (2011), 22 (11), 2263-2270CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    1,2,4,5-Tetrazines have been established as effective dienes for inverse electron demand [4 + 2] Diels-Alder cycloaddn. reactions with strained alkenes for over 50 years. Recently, this reaction pair combination has been applied to bioorthogonal labeling and cell detection applications; however, to date, there has been no detailed examn. and optimization of tetrazines for use in biol. expts. Here, we report the synthesis and characterization of 12 conjugatable tetrazines. The tetrazines were all synthesized in a similar fashion and were screened in parallel to identify candidates most ideally suited for biol. studies. In depth follow-up studies revealed compds. with varying degrees of stability and reactivity that could each be useful in different bioorthogonal applications. One promising, highly stable, and water-sol. deriv. was used in pretargeted cancer cell labeling studies, confirming its utility as a bioorthogonal moiety.
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  20. 20
    Reiner, T. and Zeglis, B. M. (2014) The inverse electron demand Diels-Alder click reaction in radiochemistry J. Labelled Compd. Radiopharm. 57, 285– 90 DOI: 10.1002/jlcr.3149
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    20
    The inverse electron demand Diels-Alder click reaction in radiochemistry
    Reiner, Thomas; Zeglis, Brian M.
    Journal of Labelled Compounds and Radiopharmaceuticals (2014), 57 (4), 285-290CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
    A review. The inverse electron-demand Diels-Alder (IEDDA) cycloaddn. between 1,2,4,5-tetrazines and strained alkene dienophiles is an emergent variety of catalyst-free 'click' chem. that has the potential to have a transformational impact on the synthesis and development of radiopharmaceuticals. The ligation is selective, rapid, high-yielding, clean, and bioorthogonal and, since its advent in 2008, has been employed in a wide variety of chem. settings. In radiochem., the reaction has proven particularly useful with 18 F and has already been utilized to create a no. of 18 F-labeled agents, including the PARP1-targeting small mol. 18 F-AZD2281, the αvβ3 integrin-targeting peptide 18 F-RGD, and the GLP-1-targeting peptide 18 F-exendin. The inherent flexibility of the ligation has also been applied to the construction of radiometal-based probes, specifically the development of a modular strategy for the synthesis of radioimmunoconjugates that effectively eliminates variability in the construction of these agents. Further, the exceptional speed and biorthogonality of the reaction have made it esp. promising in the realm of in vivo pretargeted imaging and therapy, and pretargeted imaging strategies based on the isotopes 111In, 18 F, and 64Cu have already proven capable of producing images with high tumor contrast and low levels of uptake in background, nontarget organs. Ultimately, the characteristics of inverse electron-demand Diels-Alder click chem. make it almost uniquely well-suited for radiochem., and although the field is young, this ligation has the potential to make a tremendous impact on the synthesis, development, and study of novel radiopharmaceuticals.
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  21. 21
    Jacobson, O., Kiesewetter, D. O., and Chen, X. (2015) Fluorine-18 Radiochemistry – Labeling Strategies and Synthetic Routes Bioconjugate Chem. 26, 1– 18 DOI: 10.1021/bc500475e
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    21
    Fluorine-18 Radiochemistry, Labeling Strategies and Synthetic Routes
    Jacobson, Orit; Kiesewetter, Dale O.; Chen, Xiaoyuan
    Bioconjugate Chemistry (2015), 26 (1), 1-18CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    A review. Fluorine-18 is the most frequently used radioisotope in positron emission tomog. (PET) radiopharmaceuticals in both clin. and preclin. research. Its phys. and nuclear characteristics (97% β+ decay, 109.7 min half-life, 635 keV positron energy), along with high specific activity and ease of large scale prodn., make it an attractive nuclide for radiochem. labeling and mol. imaging. Versatile chem. including nucleophilic and electrophilic substitutions allows direct or indirect introduction of 18F into mols. of interest. The significant increase in 18F radiotracers for PET imaging accentuates the need for simple and efficient 18F-labeling procedures. In this review, we will describe the current radiosynthesis routes and strategies for 18F labeling of small mols. and biomols.
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  22. 22
    Wyffels, L., Thomae, D., Waldron, A., Fissers, J., Dedeurwaerdere, S., Van den Veken, P., Joossens, J., Stroobants, K., Augustyns, K., and Staelens, S. (2014) In vivo evaluation of 18F-labeled TCO for pre-targeted PET imaging in the brain Nucl. Med. Biol. 41, 513– 523 DOI: 10.1016/j.nucmedbio.2014.03.023
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    22
    In vivo evaluation of 18F-labeled TCO for pre-targeted PET imaging in the brain
    wyffels, Leonie; Thomae, David; Waldron, Ann-Marie; Fissers, Jens; Dedeurwaerdere, Stefanie; Van der Veken, Pieter; Joossens, Jurgen; Stroobants, Sigrid; Augustyns, Koen; Staelens, Steven
    Nuclear Medicine and Biology (2014), 41 (6), 513-523CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)
    The tetrazine-trans-cylooctene cycloaddn. using radiolabeled tetrazine or radiolabeled trans-cyclooctene (TCO) has been reported to be a very fast, selective and bioorthogonal reaction that could be useful for in vivo radiolabeling of mols. We wanted to evaluate the in vivo biodistribution profile and brain uptake of 18F-labeled TCO ([18F]TCO) to assess its potential for pre-targeted imaging in the brain. We evaluated the in vivo behavior of [18F]TCO via an ex vivo biodistribution study complemented by in vivo μPET imaging at 5, 30, 60, 90, 120 and 240 min post tracer injection. An in vivo metabolite study was performed at 5 min, 30 min and 120 min post [18F]TCO injection by RP-HPLC anal. of plasma and brain exts. Incubation with human liver microsomes was performed to further evaluate the metabolite profile of the tracer. μPET imaging and ex-vivo biodistribution revealed an high initial brain uptake of [18F]TCO (3.8%ID/g at 5 min pi) followed by a washout to 3.0%ID/g at 30 min pi. Subsequently the brain uptake increased again to 3.7%ID/g at 120 min pi followed by a slow washout until 240 min pi (2.9%ID/g). Autoradiog. confirmed homogenous brain uptake. On the μPET images bone uptake became gradually visible after 120 min pi and was clearly visible at 240 min pi. The metabolite study revealed a fast metabolization of [18F]TCO in plasma and brain into three main polar radiometabolites. Although [18F]TCO has previously been described to be a useful tracer for radiolabeling of tetrazine modified targeting mols., our study indicates that its utility for in vivo chem. and pre-targeted imaging will be limited. Although [18F]TCO clearly enters the brain, it is quickly metabolized with a non-specific accumulation of radioactivity in the brain and bone.
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  23. 23
    Viola-Villegas, N. T., Rice, S. L., Carlin, S., Wu, X., Evans, M. J., Sevak, K. K., Drobjnak, M., Ragupathi, G., Sawada, R., and Scholz 2013, Applying PET to broaden the diagnostic utility of the clinically validated CA19.9 serum biomarker for oncology J. Nucl. Med. 54, 1876– 1882 DOI: 10.2967/jnumed.113.119867
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    Applying PET to broaden the diagnostic utility of the clinically validated CA19.9 serum biomarker for oncology
    Viola-Villegas, Nerissa Therese; Rice, Samuel L.; Carlin, Sean; Wu, Xiaohong; Evans, Michael J.; Sevak, Kuntal K.; Drobjnak, Marija; Ragupathi, Govind; Sawada, Ritsuko; Scholz, Wolfgang W.; Livingston, Philip O.; Lewis, Jason S.
    Journal of Nuclear Medicine (2013), 54 (11), 1876-1882CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)
    Despite their considerable advantages, many circulating biomarkers have well-documented limitations. One prominent shortcoming in oncol. is a high frequency of false-pos. indications for malignant disease in upfront diagnosis. Because one common cause of false positivism is biomarker prodn. from benign disorders in unrelated host tissues, we hypothesized that probing the sites of biomarker secretion with an imaging tool could be a broadly useful strategy to deconvolute the meaning of foreboding but inconclusive circulating biomarker levels. Methods: In prepn. to address this hypothesis clin., we developed 89Zr-5B1, a fully human, antibody-based radiotracer targeting tumor-assocd. CA19.9 in the preclin. setting. Results: 89Zr-5B1 localized to multiple tumor models representing diseases with undetectable and supraphysiol. serum CA19.9 levels. Among these, 89Zr-5B1 detected orthotopic models of pancreatic ductal adenocarcinoma, an elusive cancer for which the serum assay is measured in humans but with limited specificity in part because of the frequency of CA19.9 secretion from benign hepatic pathologies. Conclusion: In this report, a general strategy to supplement some of the shortcomings of otherwise highly useful circulating biomarkers with immunoPET is described. To expedite the clin. validation of this model, a human monoclonal antibody to CA19.9 (a highly visible but partially flawed serum biomarker for several cancers) was radiolabeled and evaluated, and the compelling preclin. evidence suggests that the radiotracer may enhance the fidelity of diagnosis and staging of pancreatic ductal adenocarcinoma, a notoriously occult cancer.
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  24. 24
    Chan, A., Prassas, I., Dimitromanolakis, A., Brand, R. E., Serra, S., Diamandis, E. P., and Blasutig, I. M. (2014) Validation of Biomarkers that complement CA19.9 in Detecting Early Pancreatic Cancer Clin. Cancer Res. 20, 5787– 95 DOI: 10.1158/1078-0432.CCR-14-0289
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    24
    Validation of Biomarkers That Complement CA19.9 in Detecting Early Pancreatic Cancer
    Chan, Alison; Prassas, Ioannis; Dimitromanolakis, Apostolos; Brand, Randall E.; Serra, Stefano; Diamandis, Eleftherios P.; Blasutig, Ivan M.
    Clinical Cancer Research (2014), 20 (22), 5787-5795CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
    Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer mortality. Carbohydrate antigen 19.9 (CA19.9), the only tumor marker available to detect and monitor PDAC, is not sufficiently sensitive and specific to consistently differentiate early cancer from benign disease. In this study, we aimed to validate recently discovered serum protein biomarkers for the early detection of PDAC and ultimately develop a biomarker panel that could discriminate PDAC from other benign disease better than the existing marker CA19.9. Patients and Methods: We performed a retrospective blinded evaluation of 400 serum samples collected from individuals recruited on a consecutive basis. The sample population consisted of 250 individuals with PDAC at various stages, 130 individuals with benign conditions and 20 healthy individuals. The serum levels of each biomarker were detd. by ELISAs or automated immunoassay. Results: By randomly splitting matched samples into a training (n = 186) and validation (n = 214) set, we were able to develop and validate a biomarker panel consisting of CA19.9, CA125, and LAMC2 that significantly improved the performance of CA19.9 alone. Improved discrimination was obsd. in the validation set between all PDAC and benign conditions (AUCCA19.9 = 0.80 vs. AUCCA19.9+CA125+LAMC2 = 0.87; P < 0.005) as well as between early-stage PDAC and benign conditions (AUCCA19.9 = 0.69 vs. AUCCA19.9+CA125+LAMC2 = 0.76; P < 0.05) and between early-stage PDAC and chronic pancreatitis (CP; AUCCA19.9 = 0.59 vs. AUCCA19.9+CA125+LAMC2 = 0.74; P < 0.05). Conclusions: The data demonstrate that a serum protein biomarker panel consisting of CA125, CA19.9, and LAMC2 is able to significantly improve upon the performance of CA19.9 alone in detecting PDAC.
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  • Abstract

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    Scheme 1

    Scheme 1. Radiochemical Synthesis of the Radioligand Tz-PEG11-Al[18F]-NOTA ([18F]2)a
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    Scheme a[18F]2 was obtained in 54–56% RCY (d.c.) and high SAs (21.4–26.7 GBq/μmol) after a total synthesis time of 108 min. Purification of the crude reaction mixture using a C18-cartridge gave [18F]2 in purities >96%.

    Figure 1

    Figure 1. Biodistribution of the radioligand [18F]2 in healthy athymic nude mice. The 18F-labeled tracer (1.33 nmol, 1.8–2.0 MBq) was injected via the tail vein before the mice were euthanized, and the organs collected at the appropriate time points.

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    Figure 2

    Figure 2. Results of the biodistribution pretargeting CA19.9 with [18F]2/5B1-TCO. Subcutaneous BxPC3 xenograft bearing mice were administered 5B1-TCO (1.33 nmol) 72 h prior to the injection of the 18F-labeled tracer (1.33 nmol, 1.8–2.0 MBq) via the tail vein before the mice were euthanized, and the organs collected at the appropriate time points.

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    Figure 3

    Figure 3. PET images of Tz-PEG11-Al[18F]-NOTA/5B1-TCO pretargeting strategy. Subcutaneous BxPC3 xenograft bearing mice were administered 5B1-TCO (1.33 nmol) 72 h prior to the injection of the 18F-labeled tracer (1.33 nmol, 18–20 MBq) via the tail vein. Transverse (top) and coronal (middle) planar images intersect the center of the tumors. The maximum intensity projections (MIPs, bottom) clearly illustrate tumor uptake after 1 h with increasing tumor-to-background ratios over the course of the experiment.

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    This article references 25 other publications.

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      Devaraj, Neal K.; Weissleder, Ralph
      Accounts of Chemical Research (2011), 44 (9), 816-827CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. Disease mechanisms are increasingly being resolved at the mol. level. Biomedical success at this scale creates synthetic opportunities for combining specifically designed orthogonal reactions in applications such as imaging, diagnostics, and therapy. For practical reasons, it would be helpful if bioorthogonal coupling reactions proceeded with extremely rapid kinetics (k > 103 M-1 s-1) and high specificity. Improving kinetics would minimize both the time and amt. of labeling agent required to maintain high coupling yields. In this Account, we discuss our recent efforts to design extremely rapid bioorthogonal coupling reactions between tetrazines and strained alkenes. These selective reactions were first used to covalently couple conjugated tetrazine near-IR-emitting fluorophores to dienophile-modified extracellular proteins on living cancer cells. Confocal fluorescence microscopy demonstrated efficient and selective labeling, and control expts. showed minimal background fluorescence. Multistep techniques were optimized to work with nanomolar concns. of labeling agent over a time scale of minutes: the result was successful real-time imaging of covalent modification. We subsequently discovered fluorogenic probes that increase in fluorescence intensity after the chem. reaction, leading to an improved signal-to-background ratio. Fluorogenic probes were used for intracellular imaging of dienophiles. We further developed strategies to react and image chemotherapeutics, such as trans-cyclooctene taxol analogs, inside living cells. Because the coupling partners are small mols. (<300 Da), they offer unique steric advantages in multistep amplification. We also describe recent success in using tetrazine reactions to label biomarkers on cells with magneto-fluorescent nanoparticles. Two-step protocols that use bioorthogonal chem. can significantly amplify signals over both one-step labeling procedures as well as two-step procedures that use more sterically hindered biotin-avidin interactions. Nanoparticles can be detected with fluorescence or magnetic resonance techniques. These strategies are now being routinely used on clin. samples for biomarker profiling to predict malignancy and patient outcome. Finally, the authors discuss recent results with tetrazine reactions used for in vivo mol. imaging applications. Rapid tetrazine cycloaddns. allow modular labeling of small mols. with the most commonly used positron emission tomog. isotope, 18F. Addnl., recent work has applied this reaction directly in vivo for the pretargeted imaging of solid tumors. Future work with tetrazine cycloaddns. will undoubtedly lead to optimized protocols, improved probes, and addnl. biomedical applications.
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    8. 8
      Emmetiere, F., Irwin, C., Viola-Villegas, N. T., Longo, V., Cheal, S. M., Zanzonico, P., Pillarsetty, N., Weber, W. A., Lewis, J. S., and Reiner, T. (2013) 18F-Labeled-Bioorthogonal Liposomes for In Vivo Targeting Bioconjugate Chem. 24, 1784– 89 DOI: 10.1021/bc400322h
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      8
      18F-Labeled-Bioorthogonal Liposomes for In Vivo Targeting
      Emmetiere, Fabien; Irwin, Christopher; Viola-Villegas, Nerissa Therese; Longo, Valerie; Cheal, Sarah M.; Zanzonico, Pat; Pillarsetty, NagaVaraKishore; Weber, Wolfgang A.; Lewis, Jason S.; Reiner, Thomas
      Bioconjugate Chemistry (2013), 24 (11), 1784-1789CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      Liposomes are attractive vehicles for the controlled release of drugs and cytotoxins and have a long-standing history in medical research and clin. practice. In addn. to established therapeutic indications, liposomes have several favorable properties for mol. imaging, including high stability and the ability to be labeled with radioisotopes, as well as paramagnetic and fluorescent contrast agents. However, long circulation times and difficulties in creating targeted liposomes have proven challenges for imaging. In this study, we have addressed these limitations using a recently developed strategy for bioorthogonal conjugation, the reaction between tetrazines and trans-cyclooctenes. By coating radiolabeled liposomes with trans-cyclooctene and pretargeting with a tetrazine coupled to a targeted peptide, we were able to selectively enhance the retention of liposomes and bind them to tumor tissue in live animals. The rapid reaction between tetrazines and trans-cyclooctenes allowed imaging to be performed with the short-lived PET tracer 18F, yielding signal-to-background activity ratios of 7:1. The covalent, bioorthogonally driven tumor-targeting of liposomes by in vivo click chem. is promising and should be explored for more selective and rapid delivery of radiodiagnostics and radiotherapeutics, two classes of drugs which particularly benefit from fast clearance, low nonspecific binding, and the assocd. reduced toxicity to kidneys and bone marrow.
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    9. 9
      Denk, C., Svatunek, D., Filip, T., Wanek, T., Lumpi, D., Froehlich, J., Kuntner, C., and Mikula, H. (2014) Development of a 18F-labeled tetrazine with favorable pharmacokinetics for bioorthogonal PET imaging Angew. Chem., Int. Ed. 53, 9655– 59 DOI: 10.1002/anie.201404277
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      9
      Development of a 18F-Labeled Tetrazine with Favorable Pharmacokinetics for Bioorthogonal PET Imaging
      Denk, Christoph; Svatunek, Dennis; Filip, Thomas; Wanek, Thomas; Lumpi, Daniel; Froehlich, Johannes; Kuntner, Claudia; Mikula, Hannes
      Angewandte Chemie, International Edition (2014), 53 (36), 9655-9659CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A low-mol.-wt. 18F-labeled tetrazine deriv. was developed as a highly versatile tool for bioorthogonal PET imaging. Prosthetic groups and undesired carrying of 18F through addnl. steps were evaded by direct 18F-fluorination of an appropriate tetrazine precursor. Reaction kinetics of the cycloaddn. with trans-cyclooctenes were investigated by applying quantum chem. calcns. and stopped-flow measurements in human plasma; the results indicated that the labeled tetrazine is suitable as a bioorthogonal probe for the imaging of dienophile-tagged (bio)mols. In vitro and in vivo investigations revealed high stability and PET/MRI in mice showed fast homogeneous biodistribution of the 18F-labeled tetrazine that also passes the blood-brain barrier. An in vivo click expt. confirmed the bioorthogonal behavior of this novel tetrazine probe. Due to favorable chem. and pharmacokinetic properties this bioorthogonal agent should find application in bioimaging and biomedical research.
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    10. 10
      Herth, M. M., Andersen, V. L., Lehel, S., Madsen, J., Knudsen, G. M., and Kristensen, J. L. (2013) Development of a 11C-labeled tetrazine for rapidtetrazine-trans-cyclooctene ligation Chem. Commun. 49, 3805– 7 DOI: 10.1039/c3cc41027g
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    11. 11
      Zeglis, B. Z., Brand, C., Abdel-Atti, D., Carnazza, K. E., Cook, B. E., Carlin, S., Reiner, T., and Lewis, J. S. (2015) Optimization of a Pretargeted Strategy for the PET Imaging of Colorectal Carcinoma via the Modulation of Radioligand Pharmacokinetics Mol. Pharmaceutics 12, 3575– 87 DOI: 10.1021/acs.molpharmaceut.5b00294
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      11
      Optimization of a Pretargeted Strategy for the PET Imaging of Colorectal Carcinoma via the Modulation of Radioligand Pharmacokinetics
      Zeglis, Brian M.; Brand, Christian; Abdel-Atti, Dalya; Carnazza, Kathryn E.; Cook, Brendon E.; Carlin, Sean; Reiner, Thomas; Lewis, Jason S.
      Molecular Pharmaceutics (2015), 12 (10), 3575-3587CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      Pretargeted PET imaging has emerged as an effective strategy for merging the exquisite selectivity of antibody-based targeting vectors with the rapid pharmacokinetics of radiolabeled small mols. We previously reported the development of a strategy for the pretargeted PET imaging of colorectal cancer based on the bioorthogonal inverse electron demand Diels-Alder reaction between a tetrazine-bearing radioligand and a transcyclooctene-modified huA33 immunoconjugate. Although this method effectively delineated tumor tissue, its clin. potential was limited by the somewhat sluggish clearance of the radioligand through the gastrointestinal tract. Herein, we report the development and in vivo validation of a pretargeted strategy for the PET imaging of colorectal carcinoma with dramatically improved pharmacokinetics. Two novel tetrazine constructs, Tz-PEG7-NOTA and Tz-SarAr, were synthesized, characterized, and radiolabeled with 64Cu in high yield (>90%) and radiochem. purity (>99%). PET imaging and biodistribution expts. in healthy mice revealed that although 64Cu-Tz-PEG7-NOTA is cleared via both the gastrointestinal and urinary tracts, 64Cu-Tz-SarAr is rapidly excreted by the renal system alone. On this basis, 64Cu-Tz-SarAr was selected for further in vivo evaluation. To this end, mice bearing A33 antigen-expressing SW1222 human colorectal carcinoma xenografts were administered huA33-TCO, and the immunoconjugate was given 24 h to accumulate at the tumor and clear from the blood, after which 64Cu-Tz-SarAr was administered via i.v. tail vein injection. PET imaging and biodistribution expts. revealed specific uptake of the radiotracer in the tumor at early time points (5.6 ± 0.7 %ID/g at 1 h p.i.), high tumor-to-background activity ratios, and rapid elimination of unclicked radioligand. Importantly, expts. with longer antibody accumulation intervals (48 and 120 h) yielded slight decreases in tumoral uptake but also concomitant increases in tumor-to-blood activity concn. ratios. This new strategy offers dosimetric benefits as well, yielding a total ED of 0.041 rem/mCi, far below the doses produced by directly labeled 64Cu-NOTA-huA33 (0.133 rem/mCi) and 89Zr-DFO-huA33 (1.54 rem/mCi). Ultimately, this pretargeted PET imaging strategy boasts a dramatically improved pharmacokinetic profile compared to our first generation system and is capable of clearly delineating tumor tissue with high image contrast at only a fraction of the radiation dose created by directly labeled radioimmunoconjugates.
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    12. 12
      McBride, W. J., D’Souza, C. A., Sharkey, R. M., Karacay, H., Chang, C., and Goldenberg, D. M. (2010) Improved 18F Labeling of Peptides with a Fluoride-Aluminum Chelate Complex Bioconjugate Chem. 21, 1331– 40 DOI: 10.1021/bc100137x
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      12
      Improved 18F Labeling of Peptides with a Fluoride-Aluminum-Chelate Complex
      McBride, William J.; D'Souza, Christopher A.; Sharkey, Robert M.; Karacay, Habibe; Rossi, Edmund A.; Chang, Chien-Hsing; Goldenberg, David M.
      Bioconjugate Chemistry (2010), 21 (7), 1331-1340CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      We reported previously the feasibility to radiolabel peptides with fluorine-18 (18F) using a rapid one-pot method that first mixes 18F- with Al3+ and then binds the (Al18F)2+ complex to a NOTA ligand on the peptide. We examd. several new NOTA ligands and detd. how temp., reaction time, and reagent concn. affected the radiolabeling yield. Four structural variations of the NOTA ligand had isolated radiolabeling yields ranging from 5.8% to 87% under similar reaction conditions. All of the Al18F NOTA complexes were stable in vitro in human serum, and those that were tested in vivo also were stable. The radiolabeling reactions were performed at 100°, and the peptides could be labeled in as little as 5 min. The IMP467 peptide could be labeled up to 115 GBq/μmol (3100 Ci/mmol), with a total reaction and purifn. time of 30 min without chromatog. purifn.
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    13. 13
      Richter, S. and Wuest, F. (2014) 18F-Labeled Peptides: The Future Is Bright Molecules 19, 20536– 56 DOI: 10.3390/molecules191220536
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      13
      18F-labeled peptides: the future is bright
      Richter, Susan; Wuest, Frank
      Molecules (2014), 19 (12), 20536-20556, 21 pp.CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
      A review. Radiolabeled peptides have been the subject of intense research efforts for targeted diagnostic imaging and radiotherapy over the last 20 years. Peptides offer several advantages for receptor imaging and targeted radiotherapy. The low mol. wt. of peptides allows for rapid clearance from the blood and non-target tissue, which results in favorable target-to-non-target ratios. Moreover, peptides usually display good tissue penetration and they are generally non-immunogenic. A major drawback is their potential low metabolic stability. The majority of currently used radiolabeled peptides for targeted mol. imaging and therapy of cancer is labeled with various radiometals like 99mTc, 68Ga, and 177Lu. However, over the last decade an increasing no. of F-labeled peptides have been reported. Despite of obvious advantages of 18F like its ease of prodn. in large quantities at high specific activity, the low β+ energy (0.64 MeV) and the favorable half-life (109.8 min), 18F-labeling of peptides remains a special challenge. The first part of this review will provide a brief overview on chem. strategies for peptide labeling with 18F. A second part will discuss recent technol. advances for 18F-labeling of peptides with special focus on microfluidic technol., automation, and kit-like prepn. of 18F-labeled peptides.
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    14. 14
      Pan, D., Yan, Y., Yang, R., Xu, Y. P., Chen, F., Wang, L., Luo, S., and Yang, M. (2014) PET imaging of prostate tumors with 18F-Al-NOTA-MATBBN Contrast Media Mol. Imaging 9, 342– 8 DOI: 10.1002/cmmi.1583
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      14
      PET imaging of prostate tumors with 18F-Al-NOTA-MATBBN
      Pan, Donghui; Yan, Yongjun; Yang, Ronghua; Xu, Yu Ping; Chen, Fei; Wang, Lizhen; Luo, Shineng; Yang, Min
      Contrast Media & Molecular Imaging (2014), 9 (5), 342-348CODEN: CMMICO; ISSN:1555-4309. (Wiley-Blackwell)
      Overexpression of the gastrin-releasing peptide receptor (GRPR) in prostate cancer provides a promising target for detection the disease. MATBBN is a new bombesin analog originating from the GRPR antagonists with a hydrophilic linker. In this study NOTA-conjugated MATBBN was labeled by the Al18F method and the potential of 18F-Al-NOTA-MATBBN for prostate tumor PET imaging was also evaluated. NOTA-MATBBN was radiolabeled with 18F using Al18F complexes. Partition coeff., in vitro stability and GRPR binding affinity were also detd. PET studies were performed with 18F-Al-NOTA-MATBBN in PC-3 tumor-bearing mice. 18F-Al-NOTA-MATBBN can be produced within 30 min with a decay-cor. yield of 62.5 ± 2.1% and a radiochem. purity of >98%. The logP octanol-water value for the Al18F-labeled BBN analog was -2.40 ± 0.07 and the radiotracer was stable in phosphate-buffered saline and human serum for 2 h. The IC50 values of displacement for the 18F-Al-NOTA-MATBBN with MATBBN was 126.9 ± 2.75 nm. The PC-3 tumors were clearly visible with high contrast after injection of the labeled peptide. At 60 min post-injection, the tumor uptakes for 18F-Al-NOTA-MATBBN and 18F-FDG were 4.59 ± 0.43 and 1.98 ± 0.35% injected dose/g, and tumor to muscle uptake radios for two tracers were 6.77 ± 1.10 and 1.78 ± 0.32, resp. Dynamic PET revealed that 18F-Al-NOTA-MATBBN was excreted mainly through the kidneys. GRPR-binding specificity was also demonstrated by reduced tumor uptake of 18F-Al-NOTA-MATBBN after coinjection with excess unlabeled MATBBN peptide at 1 h post-injection. NOTA- MATBBN could be labeled rapidly with 18F using one step method. 18F-Al-NOTA-MATBBN may be a promising PET imaging agent for prostate cancer. Copyright © 2014 John Wiley & Sons, Ltd.
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    15. 15
      McBride, W. J., Sharkey, R. M., Karacay, H., D’Souza, C. A., Rossi, E. A., Laverman, P., Chang, C., Boerman, O. C., and Goldenberg, D. M. (2009) A novel method for 18F Radiolabeling for PET J. Nucl. Med. 50, 991– 8 DOI: 10.2967/jnumed.108.060418
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      There is no corresponding record for this reference.
    16. 16
      McBride, W. J., D’Souza, C. A., Karacay, H., Sharkey, R. M., and Goldenberg, D. M. (2012) New Lyophilized Kit for Rapid Radiofluorination of Peptides Bioconjugate Chem. 23, 538– 47 DOI: 10.1021/bc200608e
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      16
      New Lyophilized Kit for Rapid Radiofluorination of Peptides
      McBride, William J.; D'Souza, Christopher A.; Karacay, Habibe; Sharkey, Robert M.; Goldenberg, David M.
      Bioconjugate Chemistry (2012), 23 (3), 538-547CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      Radiolabeling compds. with positron-emitting radionuclides often involves a time-consuming, customized process. Herein, we report a simple lyophilized kit formulation for labeling peptides with 18F, based on the aluminum-fluoride procedure. The prototype kit contains IMP485, a NODA (1,4,7-triazacyclononane-1,4-diacetate)-MPAA (Me phenylacetic acid)-di-HSG (histamine-succinyl-glycine) hapten-peptide, [NODA-MPAA-d-Lys(HSG)-d-Tyr-d-Lys(HSG)-NH2], used for pretargeting, but we also examd. a similar kit formulation for a somatostatin-binding peptide [IMP466, NOTA-d-Phe-Cys-Phe-d-Trp-Lys-Thr-Cys-Throl] bearing a NOTA ligand to det. if the benefits of using a kit can be extended to other AlF-binding peptides. The NODA-MPAA ligand forms a single stable complex with (AlF)2+ in high yields. In order to establish suitable conditions for a facile kit, the formulation was optimized for pH, peptide to Al3+ ratio, bulking agent, radioprotectant, and the buffer. For optimal labeling, the kit was reconstituted with an aq. soln. of 18F- and ethanol (1:1), heated at 100-110 °C for 15 min, and then simply and rapidly purified using one of two equally effective solid-phase extn. (SPE) methods. Al18F-IMP485 was isolated as a single isomer complex, in high yield (45-97%) and high specific activity (up to 223 GBq/μmol), within 20 min. The labeled product was stable in human serum at 37 °C for 4 h and in vivo, urine samples showed the intact product was eliminated. Tumor targeting of the Al18F-IMP485 in nude mice bearing human colon cancer xenografts pretargeted with an anti-CEACAM5 bispecific antibody showed very low uptake (0.06% ± 0.02 ID/g) in bone, further illustrating its stability. At 1 h, pretargeted animals had high Al18F-IMP485 tumor uptake (28.1% ± 4.5 ID/g), with ratios of 9 ± 4, 123 ± 38, 110 ± 43, and 120 ± 108 for kidney, liver, blood and bone, resp. Tumor uptake remained high at 3 h postinjection, with increased tumor/nontumor ratios. The NOTA-somatostatin-binding peptide also was fluorinated with good yield and high specific activity in the same kit formulation. However, yields were somewhat lower than those achieved with IMP485 contg. the NODA-MPAA ligand, likely reflecting this ligand's superior binding properties over the simple NOTA. These studies indicate that 18F-labeled peptides can be reproducibly prepd. as stable Al-F complexes with good radiochem. yield and high specific activity using a simple, one-step, lyophilized kit followed by a rapid purifn. by SPE that provides the 18F-peptide ready for patient injection within 30 min.
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    17. 17
      Hoigebazar, L., Jeong, J. M., Lee, J., Shetty, D., Yang, B. Y., Lee, Y., Lee, D. S., Chung, J., and Lee, M. C. (2012) Syntheses of 2-Nitroimidazole Derivatives Conjugated with 1,4,7-Tiazacyclononae-N,N′-Diacetic Acid Labeled with F-18 Using an Aluminum Complex Method for Hypoxia Imaging J. Med. Chem. 55, 3155– 62 DOI: 10.1021/jm201611a
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    18. 18
      Zeglis, B. M., Emmetiere, F., Pillarsetty, N., Weissleder, R., Lewis, J. S., and Reiner, T. (2014) Building Blocks for the Construction of Bioorthogonally Reactive Peptides via Solid Phase Peptide Synthesis ChemistryOpen 3, 48– 53 DOI: 10.1002/open.201402000
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    19. 19
      Karver, M. R., Weissleder, R., and Hilderbrand, S. A. (2011) Synthesis and evaluation of a series of 1,2,4,5-tetrazines for bioorthogonal conjugation Bioconjugate Chem. 22, 2263– 70 DOI: 10.1021/bc200295y
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      19
      Synthesis and evaluation of a series of 1,2,4,5-tetrazines for bioorthogonal conjugation
      Karver, Mark R.; Weissleder, Ralph; Hilderbrand, Scott A.
      Bioconjugate Chemistry (2011), 22 (11), 2263-2270CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      1,2,4,5-Tetrazines have been established as effective dienes for inverse electron demand [4 + 2] Diels-Alder cycloaddn. reactions with strained alkenes for over 50 years. Recently, this reaction pair combination has been applied to bioorthogonal labeling and cell detection applications; however, to date, there has been no detailed examn. and optimization of tetrazines for use in biol. expts. Here, we report the synthesis and characterization of 12 conjugatable tetrazines. The tetrazines were all synthesized in a similar fashion and were screened in parallel to identify candidates most ideally suited for biol. studies. In depth follow-up studies revealed compds. with varying degrees of stability and reactivity that could each be useful in different bioorthogonal applications. One promising, highly stable, and water-sol. deriv. was used in pretargeted cancer cell labeling studies, confirming its utility as a bioorthogonal moiety.
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    20. 20
      Reiner, T. and Zeglis, B. M. (2014) The inverse electron demand Diels-Alder click reaction in radiochemistry J. Labelled Compd. Radiopharm. 57, 285– 90 DOI: 10.1002/jlcr.3149
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      20
      The inverse electron demand Diels-Alder click reaction in radiochemistry
      Reiner, Thomas; Zeglis, Brian M.
      Journal of Labelled Compounds and Radiopharmaceuticals (2014), 57 (4), 285-290CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
      A review. The inverse electron-demand Diels-Alder (IEDDA) cycloaddn. between 1,2,4,5-tetrazines and strained alkene dienophiles is an emergent variety of catalyst-free 'click' chem. that has the potential to have a transformational impact on the synthesis and development of radiopharmaceuticals. The ligation is selective, rapid, high-yielding, clean, and bioorthogonal and, since its advent in 2008, has been employed in a wide variety of chem. settings. In radiochem., the reaction has proven particularly useful with 18 F and has already been utilized to create a no. of 18 F-labeled agents, including the PARP1-targeting small mol. 18 F-AZD2281, the αvβ3 integrin-targeting peptide 18 F-RGD, and the GLP-1-targeting peptide 18 F-exendin. The inherent flexibility of the ligation has also been applied to the construction of radiometal-based probes, specifically the development of a modular strategy for the synthesis of radioimmunoconjugates that effectively eliminates variability in the construction of these agents. Further, the exceptional speed and biorthogonality of the reaction have made it esp. promising in the realm of in vivo pretargeted imaging and therapy, and pretargeted imaging strategies based on the isotopes 111In, 18 F, and 64Cu have already proven capable of producing images with high tumor contrast and low levels of uptake in background, nontarget organs. Ultimately, the characteristics of inverse electron-demand Diels-Alder click chem. make it almost uniquely well-suited for radiochem., and although the field is young, this ligation has the potential to make a tremendous impact on the synthesis, development, and study of novel radiopharmaceuticals.
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    21. 21
      Jacobson, O., Kiesewetter, D. O., and Chen, X. (2015) Fluorine-18 Radiochemistry – Labeling Strategies and Synthetic Routes Bioconjugate Chem. 26, 1– 18 DOI: 10.1021/bc500475e
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      21
      Fluorine-18 Radiochemistry, Labeling Strategies and Synthetic Routes
      Jacobson, Orit; Kiesewetter, Dale O.; Chen, Xiaoyuan
      Bioconjugate Chemistry (2015), 26 (1), 1-18CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
      A review. Fluorine-18 is the most frequently used radioisotope in positron emission tomog. (PET) radiopharmaceuticals in both clin. and preclin. research. Its phys. and nuclear characteristics (97% β+ decay, 109.7 min half-life, 635 keV positron energy), along with high specific activity and ease of large scale prodn., make it an attractive nuclide for radiochem. labeling and mol. imaging. Versatile chem. including nucleophilic and electrophilic substitutions allows direct or indirect introduction of 18F into mols. of interest. The significant increase in 18F radiotracers for PET imaging accentuates the need for simple and efficient 18F-labeling procedures. In this review, we will describe the current radiosynthesis routes and strategies for 18F labeling of small mols. and biomols.
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    22. 22
      Wyffels, L., Thomae, D., Waldron, A., Fissers, J., Dedeurwaerdere, S., Van den Veken, P., Joossens, J., Stroobants, K., Augustyns, K., and Staelens, S. (2014) In vivo evaluation of 18F-labeled TCO for pre-targeted PET imaging in the brain Nucl. Med. Biol. 41, 513– 523 DOI: 10.1016/j.nucmedbio.2014.03.023
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      22
      In vivo evaluation of 18F-labeled TCO for pre-targeted PET imaging in the brain
      wyffels, Leonie; Thomae, David; Waldron, Ann-Marie; Fissers, Jens; Dedeurwaerdere, Stefanie; Van der Veken, Pieter; Joossens, Jurgen; Stroobants, Sigrid; Augustyns, Koen; Staelens, Steven
      Nuclear Medicine and Biology (2014), 41 (6), 513-523CODEN: NMBIEO; ISSN:0969-8051. (Elsevier)
      The tetrazine-trans-cylooctene cycloaddn. using radiolabeled tetrazine or radiolabeled trans-cyclooctene (TCO) has been reported to be a very fast, selective and bioorthogonal reaction that could be useful for in vivo radiolabeling of mols. We wanted to evaluate the in vivo biodistribution profile and brain uptake of 18F-labeled TCO ([18F]TCO) to assess its potential for pre-targeted imaging in the brain. We evaluated the in vivo behavior of [18F]TCO via an ex vivo biodistribution study complemented by in vivo μPET imaging at 5, 30, 60, 90, 120 and 240 min post tracer injection. An in vivo metabolite study was performed at 5 min, 30 min and 120 min post [18F]TCO injection by RP-HPLC anal. of plasma and brain exts. Incubation with human liver microsomes was performed to further evaluate the metabolite profile of the tracer. μPET imaging and ex-vivo biodistribution revealed an high initial brain uptake of [18F]TCO (3.8%ID/g at 5 min pi) followed by a washout to 3.0%ID/g at 30 min pi. Subsequently the brain uptake increased again to 3.7%ID/g at 120 min pi followed by a slow washout until 240 min pi (2.9%ID/g). Autoradiog. confirmed homogenous brain uptake. On the μPET images bone uptake became gradually visible after 120 min pi and was clearly visible at 240 min pi. The metabolite study revealed a fast metabolization of [18F]TCO in plasma and brain into three main polar radiometabolites. Although [18F]TCO has previously been described to be a useful tracer for radiolabeling of tetrazine modified targeting mols., our study indicates that its utility for in vivo chem. and pre-targeted imaging will be limited. Although [18F]TCO clearly enters the brain, it is quickly metabolized with a non-specific accumulation of radioactivity in the brain and bone.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXntFCqsbc%253D&md5=7cef1f4d41f9297223eebc97437169da
    23. 23
      Viola-Villegas, N. T., Rice, S. L., Carlin, S., Wu, X., Evans, M. J., Sevak, K. K., Drobjnak, M., Ragupathi, G., Sawada, R., and Scholz 2013, Applying PET to broaden the diagnostic utility of the clinically validated CA19.9 serum biomarker for oncology J. Nucl. Med. 54, 1876– 1882 DOI: 10.2967/jnumed.113.119867
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      23
      Applying PET to broaden the diagnostic utility of the clinically validated CA19.9 serum biomarker for oncology
      Viola-Villegas, Nerissa Therese; Rice, Samuel L.; Carlin, Sean; Wu, Xiaohong; Evans, Michael J.; Sevak, Kuntal K.; Drobjnak, Marija; Ragupathi, Govind; Sawada, Ritsuko; Scholz, Wolfgang W.; Livingston, Philip O.; Lewis, Jason S.
      Journal of Nuclear Medicine (2013), 54 (11), 1876-1882CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)
      Despite their considerable advantages, many circulating biomarkers have well-documented limitations. One prominent shortcoming in oncol. is a high frequency of false-pos. indications for malignant disease in upfront diagnosis. Because one common cause of false positivism is biomarker prodn. from benign disorders in unrelated host tissues, we hypothesized that probing the sites of biomarker secretion with an imaging tool could be a broadly useful strategy to deconvolute the meaning of foreboding but inconclusive circulating biomarker levels. Methods: In prepn. to address this hypothesis clin., we developed 89Zr-5B1, a fully human, antibody-based radiotracer targeting tumor-assocd. CA19.9 in the preclin. setting. Results: 89Zr-5B1 localized to multiple tumor models representing diseases with undetectable and supraphysiol. serum CA19.9 levels. Among these, 89Zr-5B1 detected orthotopic models of pancreatic ductal adenocarcinoma, an elusive cancer for which the serum assay is measured in humans but with limited specificity in part because of the frequency of CA19.9 secretion from benign hepatic pathologies. Conclusion: In this report, a general strategy to supplement some of the shortcomings of otherwise highly useful circulating biomarkers with immunoPET is described. To expedite the clin. validation of this model, a human monoclonal antibody to CA19.9 (a highly visible but partially flawed serum biomarker for several cancers) was radiolabeled and evaluated, and the compelling preclin. evidence suggests that the radiotracer may enhance the fidelity of diagnosis and staging of pancreatic ductal adenocarcinoma, a notoriously occult cancer.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvVClsrzO&md5=0333e8ca3fc2e3ce9ec6ebab9950414e
    24. 24
      Chan, A., Prassas, I., Dimitromanolakis, A., Brand, R. E., Serra, S., Diamandis, E. P., and Blasutig, I. M. (2014) Validation of Biomarkers that complement CA19.9 in Detecting Early Pancreatic Cancer Clin. Cancer Res. 20, 5787– 95 DOI: 10.1158/1078-0432.CCR-14-0289
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      24
      Validation of Biomarkers That Complement CA19.9 in Detecting Early Pancreatic Cancer
      Chan, Alison; Prassas, Ioannis; Dimitromanolakis, Apostolos; Brand, Randall E.; Serra, Stefano; Diamandis, Eleftherios P.; Blasutig, Ivan M.
      Clinical Cancer Research (2014), 20 (22), 5787-5795CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
      Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer mortality. Carbohydrate antigen 19.9 (CA19.9), the only tumor marker available to detect and monitor PDAC, is not sufficiently sensitive and specific to consistently differentiate early cancer from benign disease. In this study, we aimed to validate recently discovered serum protein biomarkers for the early detection of PDAC and ultimately develop a biomarker panel that could discriminate PDAC from other benign disease better than the existing marker CA19.9. Patients and Methods: We performed a retrospective blinded evaluation of 400 serum samples collected from individuals recruited on a consecutive basis. The sample population consisted of 250 individuals with PDAC at various stages, 130 individuals with benign conditions and 20 healthy individuals. The serum levels of each biomarker were detd. by ELISAs or automated immunoassay. Results: By randomly splitting matched samples into a training (n = 186) and validation (n = 214) set, we were able to develop and validate a biomarker panel consisting of CA19.9, CA125, and LAMC2 that significantly improved the performance of CA19.9 alone. Improved discrimination was obsd. in the validation set between all PDAC and benign conditions (AUCCA19.9 = 0.80 vs. AUCCA19.9+CA125+LAMC2 = 0.87; P < 0.005) as well as between early-stage PDAC and benign conditions (AUCCA19.9 = 0.69 vs. AUCCA19.9+CA125+LAMC2 = 0.76; P < 0.05) and between early-stage PDAC and chronic pancreatitis (CP; AUCCA19.9 = 0.59 vs. AUCCA19.9+CA125+LAMC2 = 0.74; P < 0.05). Conclusions: The data demonstrate that a serum protein biomarker panel consisting of CA125, CA19.9, and LAMC2 is able to significantly improve upon the performance of CA19.9 alone in detecting PDAC.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFGgsL%252FE&md5=a774125e63075157e4f8111d40330e38
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      Houghton, J. L., Zeglis, B. M., Abdel-Atti, D., Sawada, R., Scholz, W. W., and Lewis, J. S. (2015) Pretargeted immunoPET imaging of CA19.9: overcoming circulating antigen and internalized targeting vector to reduce radiation doses. J. Nucl. Med. [Online early access]. DOI:  DOI: 10.2967/jnumed.115.163824 . Published Online: Oct 15, 2015. http://jnm.snmjournals.org/content/early/2015/10/14/jnumed.115.163824.long (accessed Oct 15, 2015).
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