Synthesis and Preclinical Evaluation of a Bispecific PSMA-617/RM2 Heterodimer Targeting Prostate Cancer

Click to copy article linkArticle link copied!

This article references 60 other publications.

1. 1

   Center, M. M.; Jemal, A.; Lortet-Tieulent, J.; Ward, E.; Ferlay, J.; Brawley, O.; Bray, F. International Variation in Prostate Cancer Incidence and Mortality Rates. Eur. Urol. 2012, 61 (6), 1079– 1092,  DOI: 10.1016/j.eururo.2012.02.054

   Google Scholar

   1

   International variation in prostate cancer incidence and mortality rates

   Center Melissa M; Jemal Ahmedin; Lortet-Tieulent Joannie; Ward Elizabeth; Ferlay Jacques; Brawley Otis; Bray Freddie

   European urology (2012), 61 (6), 1079-92 ISSN:.

   CONTEXT: Wide variation exists internationally for prostate cancer (PCa) rates due to differences in detection practices, treatment, and lifestyle and genetic factors. OBJECTIVE: We present contemporary variations in PCa incidence and mortality patterns across five continents using the most recent data from the International Agency for Research on Cancer. EVIDENCE ACQUISITION: PCa incidence and mortality estimates for 2008 from GLOBOCAN are presented. We also examine recent trends in PCa incidence rates for 40 countries and mortality rates for 53 countries from 1985 and onward via join-point analyses using an augmented version of Cancer Incidence in Five Continents and the World Health Organization mortality database. EVIDENCE SYNTHESIS: Estimated PCa incidence rates remain most elevated in the highest resource counties worldwide including North America, Oceania, and western and northern Europe. Mortality rates tend to be higher in less developed regions of the world including parts of South America, the Caribbean, and sub-Saharan Africa. Increasing PCa incidence rates during the most recent decade were observed in 32 of the 40 countries examined, whereas trends tended to stabilize in 8 countries. In contrast, PCa mortality rates decreased in 27 of the 53 countries under study, whereas rates increased in 16 and remained stable in 10 countries. CONCLUSIONS: PCa incidence rates increased in nearly all countries considered in this analysis except in a few high-income countries. In contrast, the increase in PCa mortality rates mainly occurred in lower resource settings, with declines largely confined to high-resource countries.
2. 2

   Jemal, A.; Siegel, R.; Xu, J.; Ward, E. Cancer Statistics, 2010. CA. Cancer J. Clin. 2010, 60 (5), 277– 300,  DOI: 10.3322/caac.20073

   Google Scholar

   2

   Cancer statistics, 2010

   Jemal Ahmedin; Siegel Rebecca; Xu Jiaquan; Ward Elizabeth

   CA: a cancer journal for clinicians (2010), 60 (5), 277-300 ISSN:.

   Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data regarding cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,529,560 new cancer cases and 569,490 deaths from cancer are projected to occur in the United States in 2010. Overall cancer incidence rates decreased in the most recent time period in both men (1.3% per year from 2000 to 2006) and women (0.5% per year from 1998 to 2006), largely due to decreases in the 3 major cancer sites in men (lung, prostate, and colon and rectum [colorectum]) and 2 major cancer sites in women (breast and colorectum). This decrease occurred in all racial/ethnic groups in both men and women with the exception of American Indian/Alaska Native women, in whom rates were stable. Among men, death rates for all races combined decreased by 21.0% between 1990 and 2006, with decreases in lung, prostate, and colorectal cancer rates accounting for nearly 80% of the total decrease. Among women, overall cancer death rates between 1991 and 2006 decreased by 12.3%, with decreases in breast and colorectal cancer rates accounting for 60% of the total decrease. The reduction in the overall cancer death rates translates to the avoidance of approximately 767,000 deaths from cancer over the 16-year period. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, geographic area, and calendar year. Although progress has been made in reducing incidence and mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons younger than 85 years. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population and by supporting new discoveries in cancer prevention, early detection, and treatment.
3. 3

   Siegel, R. L.; Miller, K. D.; Jemal, A. Cancer Statistics, 2020. CA. Cancer J. Clin. 2020, 70 (1), 7– 30,  DOI: 10.3322/caac.21590

   Google Scholar

   3

   Cancer statistics, 2020

   Siegel Rebecca L; Miller Kimberly D; Jemal Ahmedin

   CA: a cancer journal for clinicians (2020), 70 (1), 7-30 ISSN:.

   Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.
4. 4

   Wolf, P. Prostate Specific Membrane Antigen as Biomarker and Therapeutic Target for Prostate Cancer. In Prostate Cancer - Diagnostic and Therapeutic Advances; Spiess, P. E., Ed.; InTech, 2011; pp 81– 100.  DOI: 10.5772/26951 .

   Google Scholar

   There is no corresponding record for this reference.
5. 5

   Davis, M. I.; Bennett, M. J.; Thomas, L. M.; Bjorkman, P. J. Crystal Structure of Prostate-Specific Membrane Antigen, a Tumor Marker and Peptidase. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (17), 5981– 5986,  DOI: 10.1073/pnas.0502101102

   Google Scholar

   5

   Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase

   Davis, Mindy I.; Bennett, Melanie J.; Thomas, Leonard M.; Bjorkman, Pamela J.

   Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (17), 5981-5986CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

   Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer cells and nonprostatic solid tumor neovasculature and is a target for anticancer imaging and therapeutic agents. PSMA acts as a glutamate carboxypeptidase (GCPII) on small mol. substrates, including folate, the anticancer drug, methotrexate, and the neuropeptide, N-acetyl-L-aspartyl-L-glutamate (α-NAAG). Here, the authors present the 3.5-Å crystal structure of the human PSMA ectodomain (residues 44-750), which revealed a homodimer with structural similarity to the transferrin receptor, a receptor for Fe-loaded transferrin that lacks protease activity. Unlike the transferrin receptor, the protease domain of PSMA contained a binuclear Zn site, catalytic residues, and a proposed substrate-binding patch of 3 Arg residues. Elucidation of the PSMA structure combined with docking studies and a proposed catalytic mechanism provided insight into the recognition of inhibitors and the natural substrate, α-NAAG. The PSMA structure will assist in facilitating the development of chemotherapeutics, cancer-imaging agents, and agents for treatment of neurol. disorders.
6. 6

   Bacich, D. J.; Pinto, J. T.; Tong, W. P.; Heston, W. D. W. Cloning, Expression, Genomic Localization, and Enzymatic Activities of the Mouse Homolog of Prostate-Specific Membrane Antigen/NAALADase/Folate Hydrolase. Mamm. Genome 2001, 12 (2), 117– 123,  DOI: 10.1007/s003350010240

   Google Scholar

   6

   Cloning, expression, genomic localization, and enzymatic activities of the mouse homolog of prostate-specific membrane antigen/NAALADase/folate hydrolase

   Bacich, Dean J.; Pinto, John T.; Tong, William P.; Heston, Warren D. W.

   Mammalian Genome (2001), 12 (2), 117-123CODEN: MAMGEC; ISSN:0938-8990. (Springer-Verlag New York Inc.)

   Human Prostate Specific Membrane Antigen (PSMA), also known as folate hydrolase I (FOLH1), is a 750-amino acid type II membrane glycoprotein, which is primarily expressed in normal human prostate epithelium and is upregulated in prostate cancer, including metastatic disease. We have cloned and sequenced the mouse homolog of PSMA, which we have termed Folh1, and have found that it is not expressed in the mouse prostate, but primarily in the brain and kidney. We have demonstrated that Folh1, like its human counterpart, is a glutamate-preferring carboxypeptidase, which has at least two enzymic activities: (1) N-acetylated α-linked L-amino dipeptidase (NAALADase), an enzyme involved in regulation of excitatory signaling in the brain, and (2) a γ-glutamyl carboxypeptidase (folate hydrolase). The 2,256-nt open reading frame of Folh1 encodes for a 752-amino acid protein, with 86% identity and 91% similarity to the human PSMA amino acid sequence. Cells transfected with Folh1 gained both NAALADase and folate hydrolase activities. Examn. of tissues for NAALADase activity correlated with the mRNA expression pattern for Folh1. Fluorescent in situ hybridization (FISH) revealed Folh1 maps to only one locus in the mouse genome, Chromosome 7D1-2.
7. 7

   Israeli, R. S.; Powell, C. T.; Corr, J. G.; Fair, W. R.; Heston, W. D. Expression of the Prostate-Specific Membrane Antigen. Cancer Res. 1994, 54 (7), 1807– 1811

   Google Scholar

   7

   Expression of the prostate-specific membrane antigen

   Israeli, Ron S.; Powell, C. Thomas; Corr, John G.; Fair, William R.; Heston, Warren D. W.

   Cancer Research (1994), 54 (7), 1807-11CODEN: CNREA8; ISSN:0008-5472.

   The authors have recently cloned a 2.65-kilobase complementary DNA (cDNA) encoding the prostate-specific membrane antigen (PSM) recognized by the 7E11-5.3 anti-prostate monoclonal antibody. Immunohistochem. anal. of the LNCaP, DU-145, and PC-3 prostate cancer cell lines for PSM expression using the 7E11-C5.3 antibody reveals intense staining in the LNCaP cells with no detectable expression in both the DU-145 and PC-3 cells. Coupled in vitro transcription/translation of the 2.65-kilobase full-length PSM cDNA yields an Mr 84,000 protein corresponding to the predicted polypeptide mol. wt. of PSM. Posttranslational modification of this protein with pancreatic canine microsomes yields the expected Mr 100,000 PSM antigen. Following transfection of PC-3 cells with the full-length PSM cDNA in a eukaryotic expression vector, the authors detected expression of the PSM glycoprotein by Western anal. using the 7E11-C5.3 monoclonal antibody. RNase protection anal. demonstrates that the expression of PSM mRNA is almost entirely prostate specific in human tissues. PSM expression appears to be highest in hormone-deprived states and is hormonally modulated by steroids, with 5-α-dihydrotestosterone down-regulating PSM expression in the human prostate cancer cell line LNCaP by 8-10-fold, testosterone down-regulating PSM by 3-4-fold, and corticosteroids showing no effect. Normal and malignant prostatic tissues consistently show high PSM expression, whereas the authors have noted heterogeneous, and at times absent, expression of PSM in benign prostatic hyperplasia. LNCaP tumors implanted and grown both orthotopically and s.c. in nude mice abundantly express PSM, providing an excellent in vivo model system to study the regulation and modulation of PSM expression.
8. 8

   Patel, O.; Shulkes, A.; Baldwin, G. S. Gastrin-Releasing Peptide and Cancer. Biochim. Biophys. Acta 2006, 1766, 23– 41,  DOI: 10.1016/j.bbcan.2006.01.003

   Google Scholar

   8

   Gastrin-releasing peptide and cancer

   Patel, Oneel; Shulkes, Arthur; Baldwin, Graham S.

   Biochimica et Biophysica Acta, Reviews on Cancer (2006), 1766 (1), 23-41CODEN: BBACEU; ISSN:0304-419X. (Elsevier B.V.)

   A review. Over the past 20 years, abundant evidence has been collected to suggest that gastrin-releasing peptide (GRP) and its receptors play an important role in the development of a variety of cancers. In fact, the detection of GRP and the GRP receptor in small cell lung carcinoma (SCLC), and the demonstration that anti-GRP antibodies inhibited proliferation in SCLC cell lines, established GRP as the prototypical autocrine growth factor. All forms of GRP are generated by processing of a 125-amino acid prohormone; recent studies indicate that C-terminal amidation of GRP18-27 is not essential for bioactivity, and that peptides derived from residues 31 to 125 of the prohormone are present in normal tissue and in tumors. GRP receptors can be divided into four classes, all of which belong to the 7 transmembrane domain family and bind GRP and/or GRP analogs with affinities in the nM range. Over-expression of GRP and its receptors has been demonstrated at both the mRNA and protein level in many types of tumors including lung, prostate, breast, stomach, pancreas and colon. GRP has also been shown to act as a potent mitogen for cancer cells of diverse origin both in vitro and in animal models of carcinogenesis. Other actions of GRP relevant to carcinogenesis include effects on morphogenesis, angiogenesis, cell migration and cell adhesion. Future prospects for the use of radiolabeled and cytotoxic GRP analogs and antagonists for cancer diagnosis and therapy appear promising.
9. 9

   Cornelio, D. B.; Roesler, R.; Schwartsmann, G. Gastrin-Releasing Peptide Receptor as a Molecular Target in Experimental Anticancer Therapy. Ann. Oncol. 2007, 18 (9), 1457– 1466,  DOI: 10.1093/annonc/mdm058

   Google Scholar

   9

   Gastrin-releasing peptide receptor as a molecular target in experimental anticancer therapy

   Cornelio D B; Roesler R; Schwartsmann G

   Annals of oncology : official journal of the European Society for Medical Oncology (2007), 18 (9), 1457-66 ISSN:0923-7534.

   Over the last two decades, several lines of experimental evidence have suggested that the gastrin-releasing peptide (GRP) may act as a growth factor in many types of cancer. For that reason, gastrin-releasing peptide receptor (GRPR) antagonists have been developed as anticancer candidate compounds, exhibiting impressive antitumoral activity both in vitro and in vivo in various murine and human tumors. In this article, the GRPR cell surface expression profile in human malignancies is reviewed aiming at the identification of potential tumor types for future clinical trials with GRP analogues and antagonists. In this review, we summarize the current literature regarding the GRPR status in human malignancies. Source data were obtained by searching all published material available through Medline, PubMed and relevant articles from 1971 to 2006. The data available demonstrated a high expression of GRPRs in a large spectrum of human cancers, demonstrating the potential relevance of this intracellular signaling pathway in various human tumor models. The GRPR may be an interesting target for therapeutic intervention in human malignancies, as carriers for cytotoxins, immunotoxins or radioactive compounds, being also a potential tool for tumor detection.
10. 10

    Dumont, R. a; Tamma, M.; Braun, F.; Borkowski, S.; Reubi, J. C.; Maecke, H.; Weber, W. a; Mansi, R. Targeted Radiotherapy of Prostate Cancer with a Gastrin-Releasing Peptide Receptor Antagonist Is Effective as Monotherapy and in Combination with Rapamycin. J. Nucl. Med. 2013, 54 (5), 762– 769,  DOI: 10.2967/jnumed.112.112169

    Google Scholar

    10

    Targeted radiotherapy of prostate cancer with a gastrin-releasing peptide receptor antagonist is effective as monotherapy and in combination with rapamycin

    Dumont, Rebecca A.; Tamma, MariaLuisa; Braun, Friederike; Borkowski, Sandra; Reubi, Jean Claude; Maecke, Helmut; Weber, Wolfgang A.; Mansi, Rosalba

    Journal of Nuclear Medicine (2013), 54 (5), 762-769CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)

    The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer and is an attractive target for radionuclide therapy. In addn., inhibition of the protein kinase mammalian target of rapamycin (mTOR) has been shown to sensitize various cancer cells to the effects of radiotherapy. Methods: To det. the effect of treatment with rapamycin and radiotherapy with a novel 177Lu-labeled GRPr antagonist (177Lu-RM2, BAY 1017858) alone and in combination, in vitro and in vivo studies were performed using the human PC-3 prostate cancer cell line. PC-3 cell proliferation and 177Lu-RM2 uptake after treatment with rapamycin were assessed in vitro. To det. the influence of rapamycin on 177Lu-RM2 tumor uptake, in vivo small-animal PET studies with 68Ga-RM2 were performed after treatment with rapamycin. To study the efficacy of 177Lu-RM2 in vivo, mice with s.c. PC-3 tumors were treated with 177Lu-RM2 alone or after pretreatment with rapamycin. Results: Stable expression of GRPr was maintained after rapamycin treatment with doses up to 4 mg/kg in vivo. Monotherapy with 177Lu-RM2 at higher doses (72 and 144 MBq) was effective in inducing complete tumor remission in 60% of treated mice. Treatment with 37 MBq of 177Lu-RM2 and rapamycin in combination led to significantly longer survival than with either agent alone. No treatment-related toxicity was obsd. Conclusion: Radiotherapy using a 177Lu-labeled GRPr antagonist alone or in combination with rapamycin was efficacious in inhibiting in vivo tumor growth and may be a promising strategy for treatment of prostate cancer.
11. 11

    Biddlecombe, G. B.; Rogers, B. E.; de Visser, M.; Parry, J. J.; de Jong, M.; Erion, J. L.; Lewis, J. S. Molecular Imaging of Gastrin-Releasing Peptide Receptor-Positive Tumors in Mice Using ⁶⁴Cu- and ⁸⁶Y-DOTA-(Pro¹,Tyr⁴)-Bombesin(1–14). Bioconjugate Chem. 2007, 18 (3), 724– 730,  DOI: 10.1021/bc060281l

    Google Scholar

    11

    Molecular Imaging of Gastrin-Releasing Peptide Receptor-Positive Tumors in Mice Using 64Cu- and 86Y-DOTA-(Pro1,Tyr4)-Bombesin(1-14)

    Biddlecombe, Grainne B.; Rogers, Buck E.; de Visser, Monique; Parry, Jesse J.; de Jong, Marion; Erion, Jack L.; Lewis, Jason S.

    Bioconjugate Chemistry (2007), 18 (3), 724-730CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)

    Bombesin is a tetradecapeptide neurohormone that binds to gastrin-releasing peptide receptors (GRPR). GRPRs have been found in a variety of cancers including invasive breast and prostate tumors. The peptide MP2346 (DOTA-(Pro1,Tyr4)-bombesin(1-14)) was designed to bind to these GRP receptors. This study was undertaken to evaluate radiolabeled MP2346 as a positron emission tomog. (PET) imaging agent. MP2346 was radiolabeled, in high radiochem. purity, with the positron-emitting nuclides 64Cu (t1/2 = 12.7 h, β+ = 19.3%, Eavg = 278 keV) and 86Y (t1/2 = 14.7 h, β+ = 33%, Eavg = 664 keV). 64Cu-MP2346 and 86Y-MP2346 were studied in vitro for cellular internalization by GRPR-expressing PC-3 (human prostate adenocarcinoma) cells. Both 64Cu- and 86Y-MP2346 were studied in vivo for tissue distribution in nude mice with PC-3 tumors. Biodistribution in PC3 tumor-bearing mice demonstrated higher tumor uptake, but lower liver retention, in animals injected with 86Y-MP2346 compared to 64Cu-MP2346. Receptor-mediated uptake was confirmed by a significant redn. in uptake in the PC-3 tumor and other receptor-rich tissues by coinjection of a blockade. Small animal PET/CT imaging was carried out in mice bearing PC-3 tumors and rats bearing AR42J tumors. It was possible to delineate PC-3 tumors in vivo with 64Cu-MP2346, but superior 86Y-MP2346-PET images were obtained due to lower uptake in clearance organs and lower background activity. The 86Y analog demonstrated excellent PET image quality in models of prostate cancer for the delineation of the GRPR-rich tumors and warrants further investigation.
12. 12

    Veerendra, B.; Sieckman, G.; Hoffman, T.; Rold, T.; Retzloff, L.; McCrate, J.; Prasanphanich, A.; Smith, C. Synthesis, Radiolabeling and In Vitro GRP Receptor Targeting Studies of ^99mTc-Triaza-X-BBN[7–14]NH 2 (X = Serylserylserine, Glycylglycylglycine, Glycylserylglycine, or Beta Alanine). Synth. React. Inorganic, Met. Nano-Metal Chem. (formerly Synth. React. Inorg. Met. Chem. 2006, 36 (6), 481– 491,  DOI: 10.1080/15533170600778075

    Google Scholar

    There is no corresponding record for this reference.
13. 13

    Sancho, V.; Di Florio, A.; Moody, T. W.; Jensen, R. T. Bombesin Receptor-Mediated Imaging and Cytotoxicity: Review and Current Status. Curr. Drug Delivery 2011, 8 (1), 79– 134,  DOI: 10.2174/156720111793663624

    Google Scholar

    There is no corresponding record for this reference.
14. 14

    Iagaru, A. Will GRPR Compete with PSMA as a Target in Prostate Cancer?. J. Nucl. Med. 2017, 58 (12), 1883– 1884,  DOI: 10.2967/jnumed.117.198192

    Google Scholar

    There is no corresponding record for this reference.
15. 15

    Dadachova, E. Cancer Therapy with Alpha-Emitters Labeled Peptides. Semin. Nucl. Med. 2010, 40 (3), 204– 208,  DOI: 10.1053/j.semnuclmed.2010.01.002

    Google Scholar

    There is no corresponding record for this reference.
16. 16

    Yao, V.; Parwani, A.; Maier, C.; Heston, W. D.; Bacich, D. J. Moderate Expression of Prostate-Specific Membrane Antigen, a Tissue Differentiation Antigen and Folate Hydrolase, Facilitates Prostate Carcinogenesis. Cancer Res. 2008, 68 (21), 9070– 9077,  DOI: 10.1158/0008-5472.CAN-08-2328

    Google Scholar

    There is no corresponding record for this reference.
17. 17

    Bařinka, C.; Rojas, C.; Slusher, B.; Pomper, M. Glutamate Carboxypeptidase II in Diagnosis and Treatment of Neurologic Disorders and Prostate Cancer. Curr. Med. Chem. 2012, 19 (6), 856– 870,  DOI: 10.2174/092986712799034888

    Google Scholar

    There is no corresponding record for this reference.
18. 18

    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 (23), 9578– 9582,  DOI: 10.1073/pnas.1106383108

    Google Scholar

    There is no corresponding record for this reference.
19. 19

    Kranzbühler, B.; Salemi, S.; Umbricht, C. A.; Müller, C.; Burger, I. A.; Sulser, T.; Eberli, D. Pharmacological Upregulation of Prostate-Specific Membrane Antigen (PSMA) Expression in Prostate Cancer Cells. Prostate 2018, 78 (10), 758– 765,  DOI: 10.1002/pros.23522

    Google Scholar

    There is no corresponding record for this reference.
20. 20

    Neels, O. C.; Kopka, K.; Liolios, C.; Afshar-Oromieh, A. Radiolabeled PSMA Inhibitors. Cancers (Basel) 2021, 13 (24), 6255,  DOI: 10.3390/cancers13246255

    Google Scholar

    There is no corresponding record for this reference.
21. 21

    Benešová, M.; Schäfer, M.; Bauder-Wüst, U.; Afshar-Oromieh, A.; Kratochwil, C.; Mier, W.; Haberkorn, U.; Kopka, K.; Eder, M. Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer. J. Nucl. Med. 2015, 56 (6), 914– 920,  DOI: 10.2967/jnumed.114.147413

    Google Scholar

    21

    Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of prostate cancer

    Benesova, Martina; Schaefer, Martin; Bauder-Wuest, Ulrike; Afshar-Oromieh, Ali; Kratochwil, Clemens; Mier, Walter; Haberkorn, Uwe; Kopka, Klaus; Eder, Matthias

    Journal of Nuclear Medicine (2015), 56 (6), 914-920CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine and Molecular Imaging)

    Despite many advances in the past years, the treatment of metastatic prostate cancer still remains challenging. In recent years, prostate-specific membrane antigen (PSMA) inhibitors were intensively studied to develop low-mol.-wt. ligands for imaging prostate cancer lesions by PET or SPECT. However, the endoradiotherapeutic use of these compds. requires optimization with regard to the radionuclide-chelating agent and the linker moiety between chelator and pharmacophore, which influence the overall pharmacokinetic properties of the resulting radioligand. In an effort to realize both detection and optimal treatment of prostate cancer, a tailor-made novel naphthyl-contg. DOTA-conjugated PSMA inhibitor has been developed. Methods: The peptidomimetic structure was synthesized by solid-phase peptide chem. and characterized using reversed-phase high-performance liq. chromatog. and matrix-assisted laser desorption/ionization mass spectrometry. Subsequent 67/68Ga and 177Lu labeling resulted in radiochem. yields of greater than 97% or greater than 99%, resp. Competitive binding and internalization expts. were performed using the PSMA-pos. LNCaP cell line. The in vivo biodistribution and dynamic small-animal PET imaging studies were investigated in BALB/c nu/nu mice bearing LNCaP xenografts. Results: The chem. modified PSMA inhibitor PSMA-617 demonstrated high radiolytic stability for at least 72 h. A high inhibition potency (equil. dissocn. const. [Ki] = 2.34 ± 2.94 nM on LNCaP; Ki = 0.37 ± 0.21 nM enzymically detd.) and highly efficient internalization into LNCaP cells were demonstrated. The small-animal PET measurements showed high tumor-to-background contrasts as early as 1 h after injection. Organ distribution revealed specific uptake in LNCaP tumors and in the kidneys 1 h after injection. With regard to therapeutic use, the compd. exhibited a rapid clearance from the kidneys from 113.3 ± 24.4 at 1 h to 2.13 ± 1.36 percentage injected dose per g at 24 h. The favorable pharmacokinetics of the mol. led to tumor-to-background ratios of 1,058 (tumor to blood) and 529 (tumor to muscle), resp., 24 h after injection. Conclusion: The tailor-made DOTA-conjugated PSMA inhibitor PSMA-617 presented here is sustainably refined and advanced with respect to its tumor-targeting and pharmacokinetic properties by systematic chem. modification of the linker region. Therefore, this radiotracer is suitable for a first-in-human theranostic application and may help to improve the clin. management of prostate cancer in the future.
22. 22

    Afshar-Oromieh, A.; Hetzheim, H.; Kratochwil, C.; Benesova, M.; Eder, M.; Neels, O. C.; Eisenhut, M.; Kübler, W.; Holland-Letz, T.; Giesel, F. L.; Mier, W.; Kopka, K.; Haberkorn, U. The Novel 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. J. Nucl. Med. 2015, 56, 1697,  DOI: 10.2967/jnumed.115.161299

    Google Scholar

    There is no corresponding record for this reference.
23. 23

    Kopka, K.; Benešová, M.; Bařinka, C.; Haberkorn, U.; Babich, J. Glu-Ureido–Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers. J. Nucl. Med. 2017, 58 (Supplement 2), 17S– 26S,  DOI: 10.2967/jnumed.116.186775

    Google Scholar

    23

    Glu-ureido-based inhibitors of prostate-specific membrane antigen: lessons learned during the development of a novel class of low-molecular-weight theranostic radiotracers

    Kopka, Klaus; Benesova, Martina; Barinka, Cyril; Haberkorn, Uwe; Babich, John

    Journal of Nuclear Medicine (2017), 58 (Suppl. 2), 17S-26SCODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)

    In recent years, several radioligands targeting prostate-specific membrane antigen (PSMA) have been clin. introduced as a new class of theranostic radiopharmaceuticals for the treatment of prostate cancer (PC). In the second decade of the 21st century, a new era in nuclear medicine was initiated by the clin. introduction of small-mol. PSMA inhibitor radioligands, 40 y after the clin. introduction of 18F-FDG. Because of the high incidence and mortality of PC, the new PSMA radioligands have already had a remarkable impact on the clin. management of PC. For the continuing clin. development and long-term success of theranostic agents, designing modern prospective clin. trials in theranostic nuclear medicine is essential. First-in-human studies with PSMA radioligands derived from small-mol. PSMA inhibitors showed highly sensitive imaging of PSMA-pos. PC by means of PET and SPECT as well as a dramatic response of metastatic castration-resistant PC after PSMA radioligand therapy. This tremendous success logically led to the initiation of prospective clin. trials with several PSMA radioligands. Meanwhile, MIP-1404, PSMA-11, 2-(3-{1-carboxy-5-[(6-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (DCFPyL), PSMA-617, PSMA-1007, and others have entered or will enter prospective clin. trials soon in several countries. The significance becomes apparent by, for example, the considerable increase in the no. of publications about PSMA-targeted PET imaging from 2013 to 2016 (e.g., a search of the Web of Science for "PSMA" AND "PET" found only 19 publications in 2013 but 218 in 2016). Closer examn. of the initial success of PC treatment with PSMA inhibitor radiotracers leads to several questions from the basic research perspective as well as from the perspective of clin. demands: What lessons have been learned regarding the design of PSMA radioligands that have already been developed. Has an acceptable compromise between optimal PSMA radioligand design and a broad range of clin. demands been reached. Can the lessons learned from multiple successes within the PSMA experience be transferred to further theranostic approaches.
24. 24

    Ristau, B. T.; O’Keefe, D. S.; Bacich, D. J. The Prostate-Specific Membrane Antigen: Lessons and Current Clinical Implications from 20 Years of Research. Urol. Oncol. 2014, 32 (3), 272– 279,  DOI: 10.1016/j.urolonc.2013.09.003

    Google Scholar

    24

    The prostate-specific membrane antigen: lessons and current clinical implications from 20 years of research

    Ristau Benjamin T; Bacich Dean J; O'Keefe Denise S

    Urologic oncology (2014), 32 (3), 272-9 ISSN:.

    OBJECTIVE: Despite a multitude of detection and treatment advances in the past 2 decades, prostate cancer remains the second leading cause of deaths due to cancer among men in the United States. Technological evolution and expanding knowledge of tumor biomarkers have invigorated exploration in prostate cancer therapeutics. Prostate-specific membrane antigen (PSMA) was one of the first prostate cancer biomarkers successfully cloned. Since then, it has been characterized as the prototypical cell-surface marker for prostate cancer and has been the subject of intense clinical inquiry. In this article, we review the relevant research in PSMA on the 20th anniversary of its cloning. METHODS AND MATERIALS: A PubMed search using the keywords "prostate-specific membrane antigen" or "glutamate carboxypeptidase II" provided 1019 results. An additional 3 abstracts were included from scientific meetings. Articles were vetted by title and abstract with emphasis placed on those with clinically relevant findings. RESULTS: Sixty articles were selected for inclusion. PSMA was discovered and cloned in 1993. Its structure and function were further delineated in the ensuing decade. Consensus sites of expression in normal physiology are prostate, kidney, nervous system, and small intestine. PSMA has been implicated in the neovasculature of several tumors including urothelial and renal cell carcinomas. In prostate cancer, expression of PSMA is directly related to the Gleason grade. PSMA has been tested both in imaging and therapeutics in a number of prostate cancer clinical trials. Several recent approaches to target PSMA include the use of small molecule inhibitors, PSMA-based immunotherapy, RNA aptamer conjugates, and PSMA-targeted prodrug therapy. Future study of PSMA in prostate cancer might focus on its intracellular functions and possible role in tumor neurogenesis. CONCLUSIONS: Twenty years from its discovery, PSMA represents a viable biomarker and treatment target in prostate cancer. Research to delineate its precise role in prostate carcinogenesis and within the therapeutic armamentarium for patients with prostate cancer remains encouraging.
25. 25

    Smith, J. C.; Sieckman, G. L.; Owen, N. K.; Hayes, D. L.; Mazuru, D. G.; Volkert, W. A.; Hoffman, T. J. Radiochemical Investigations of [¹⁸⁸Re(H₂O)(CO)₃-Diaminopropionic Acid-SSS-Bombesin(7–14)NH2]: Syntheses, Radiolabeling and in Vitro/in Vivo GRP Receptor Targeting Studies. Anticancer Res. 2003, 23 (1A), 63– 70

    Google Scholar

    There is no corresponding record for this reference.
26. 26

    Reubi, J. C.; Maecke, H. R. Peptide-Based Probes for Cancer Imaging. J. Nucl. Med. 2008, 49 (11), 1735– 1738,  DOI: 10.2967/jnumed.108.053041

    Google Scholar

    26

    Peptide-based probes for cancer imaging

    Reubi, Jean Claude; Maecke, Helmut R.

    Journal of Nuclear Medicine (2008), 49 (11), 1735-1738CODEN: JNMEAQ; ISSN:0161-5505. (Society of Nuclear Medicine)

    A review. Receptors for regulatory peptides are overexpressed in a variety of human cancers. They represent the mol. basis for in vivo imaging with radiolabeled peptide probes. Somatostatin-derived tracers, designed to image the sst2-overexpressing neuroendocrine tumors, have enjoyed almost 2 decades of successful development and extensive clin. applications. More recent developments include second- and third-generation somatostatin analogs, with a broader receptor subtype profile or with antagonistic properties. Emerging tracers for other peptide receptors, including cholecystokinin/gastrin and GLP-1 analogs for neuroendocrine tumors, bombesin and neuropeptide-Y analogs for prostate or breast cancers, or Arg-Gly-Asp peptides for neoangiogenesis labeling, are also in current development. Application fields include both SPECT/CT and PET/CT.
27. 27

    Maecke, H.; Hofmann, M.; Haberkorn, U. 68Ga-Labeled Peptides in Tumor Imaging. J. Nucl. Med. 2005, 46 (1 (Suppl)), 172S– 178S

    Google Scholar

    There is no corresponding record for this reference.
28. 28

    Nagasaki, S.; Nakamura, Y.; Maekawa, T.; Akahira, J.; Miki, Y.; Suzuki, T.; Ishidoya, S.; Arai, Y.; Sasano, H. Immunohistochemical Analysis of Gastrin-Releasing Peptide Receptor (GRPR) and Possible Regulation by Estrogen Receptor Bcx in Human Prostate Carcinoma. Neoplasma 2012, 59 (2), 224– 232,  DOI: 10.4149/neo_2012_029

    Google Scholar

    There is no corresponding record for this reference.
29. 29

    Liolios, C.; Patsis, C.; Bauder-Wuest, U.; Scholl, C.; Eder, M.; Kopka, K. Relations between PSMA and GRP Receptor Expression in Prostate and Breast Cancer Cell Lines for Tumor Imaging. J. Nucl. Med. 2017, 58 (Supplement 1), 929– 929

    Google Scholar

    There is no corresponding record for this reference.
30. 30

    Mansi, R.; Wang, X.; Forrer, F.; Waser, B.; Cescato, R.; Graham, K.; Borkowski, S.; Reubi, J. C.; Maecke, H. R. Development of a Potent DOTA-Conjugated Bombesin Antagonist for Targeting GRPr-Positive Tumours. Eur. J. Nucl. Med. Mol. Imaging 2011, 38 (1), 97– 107,  DOI: 10.1007/s00259-010-1596-9

    Google Scholar

    30

    Development of a potent DOTA-conjugated bombesin antagonist for targeting GRPr-positive tumours

    Mansi, Rosalba; Wang, Xuejuan; Forrer, Flavio; Waser, Beatrice; Cescato, Renzo; Graham, Keith; Borkowski, Sandra; Reubi, Jean Claude; Maecke, Helmut R.

    European Journal of Nuclear Medicine and Molecular Imaging (2011), 38 (1), 97-107CODEN: EJNMA6; ISSN:1619-7070. (Springer)

    Purpose: Radiolabeled somatostatin-based antagonists show a higher uptake in tumor-bearing mouse models than agonists of similar or even distinctly higher receptor affinity. Very similar results were obtained with another family of G protein-coupled receptor ligands, the bombesin family. We describe a new conjugate, RM2, with the chelator DOTA coupled to D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 via the cationic spacer 4-amino-1-carboxymethyl-piperidine for labeling with radiometals such as 111In and 68Ga. Methods: RM2 was synthesized on a solid support and evaluated in vitro in PC-3 cells. IC50 and Kd values were detd. The antagonist potency was evaluated by immunofluorescence-based internalization and Ca2+ mobilization assays. Biodistribution studies were performed in PC-3 and LNCaP tumor-bearing mice with 111In-RM2 and 68Ga-RM2, resp. PET/CT studies were performed on PC-3 and LNCaP tumor-bearing nude mice with 68Ga-RM2. Results: RM2 and 111In-RM2 are high-affinity and selective ligands for the GRP receptor (7.7±3.3 nmol/l for RM2; 9.3±3.3 nmol/l for natIn-RM2). The potent antagonistic properties were confirmed by an immunofluorescence-based internalization and Ca2+ mobilization assays. 68Ga- and 111In-RM2 showed high and specific uptake in both the tumor and the pancreas. Uptake in the tumor remained high (15.2±4.8%IA/g at 1 h; 11.7±2.4%IA/g at 4 h), whereas a relatively fast washout from the pancreas and the other abdominal organs was obsd. Uptake in the pancreas decreased rapidly from 22.6±4.7%IA/g at 1 h to 1.5±0.5%IA/g at 4 h. Conclusion: RM2 was shown to be a potent GRPr antagonist. Pharmacokinetics and imaging studies indicate that 111In-RM2 and 68Ga-RM2 are ideal candidates for clin. SPECT and PET studies.
31. 31

    Stoykow, C.; Erbes, T.; Maecke, H. R.; Bulla, S.; Bartholomä, M.; Mayer, S.; Drendel, V.; Bronsert, P.; Werner, M.; Gitsch, G.; Weber, W. A.; Stickeler, E.; Meyer, P. T. Gastrin-Releasing Peptide Receptor Imaging in Breast Cancer Using the Receptor Antagonist 68 Ga-RM2 And PET. Theranostics 2016, 6 (10), 1641– 1650,  DOI: 10.7150/thno.14958

    Google Scholar

    31

    Gastrin-releasing peptide receptor imaging in breast cancer using the receptor antagonist 68Ga-RM2 And PET

    Stoykow, Christian; Erbes, Thalia; Maecke, Helmut R.; Bulla, Stefan; Bartholomae, Mark; Mayer, Sebastian; Drendel, Vanessa; Bronsert, Peter; Werner, Martin; Gitsch, Gerald; Weber, Wolfgang A.; Stickeler, Elmar; Meyer, Philipp T.

    Theranostics (2016), 6 (10), 1641-1650CODEN: THERDS; ISSN:1838-7640. (Ivyspring International Publisher)

    Introduction: The gastrin-releasing peptide receptor (GRPR) is overexpressed in breast cancer. The present study evaluates GRPR imaging as a novel imaging modality in breast cancer by employing positron emission tomog. (PET) and the GRPR antagonist 68Ga-RM2. Methods: Fifteen female patients with biopsy confirmed primary breast carcinoma (3 bilateral tumors; median clin. stage IIB) underwent 68Ga-RM2-PET/CT for pretreatment staging. In vivo tumor uptake of 68Ga-RM2 was correlated with estrogen (ER) and progesterone (PR) receptor expression, HER2/neu status and MIB-1 proliferation index in breast core biopsy specimens. Results: 13/18 tumors demonstrated strongly increased 68Ga-RM2 uptake compared to normal breast tissue (defined as PET-pos.). All PET-pos. primary tumors were ER- and PR-pos. (13/13) in contrast to only 1/5 PET-neg. tumors. In a multivariate anal. including ER, PR, HER2/neu and MIB-1, only ER expression predicted 68Ga-RM2 uptake (model: r2=0.55, p=0.025). Normal breast tissue showed inter- and intraindividually variable, moderate GRPR binding (SUVMAX 2.3±1.0), while physiol. uptake of other organs was considerably less except pancreas. Of note, 68Ga-RM2-PET/CT detected internal mammary lymph nodes with high 68Ga-RM2 uptake (n=8), a contralateral axillary lymph node metastasis (verified by biopsy) and bone metastases (n=1; not detected by bone scan and CT).
32. 32

    Marusyk, A.; Polyak, K. Tumor Heterogeneity: Causes and Consequences. Biochim. Biophys. Acta - Rev. Cancer 2010, 1805 (1), 105– 117,  DOI: 10.1016/j.bbcan.2009.11.002

    Google Scholar

    32

    Tumor heterogeneity: Causes and consequences

    Marusyk, Andriy; Polyak, Kornelia

    Biochimica et Biophysica Acta, Reviews on Cancer (2010), 1805 (1), 105-117CODEN: BBACEU; ISSN:0304-419X. (Elsevier B.V.)

    A review. With rare exceptions, spontaneous tumors originate from a single cell. Yet, at the time of clin. diagnosis, the majority of human tumors display startling heterogeneity in many morphol. and physiol. features, such as expression of cell surface receptors, proliferative and angiogenic potential. To a substantial extent, this heterogeneity might be attributed to morphol. and epigenetic plasticity, but there is also strong evidence for the co-existence of genetically divergent tumor cell clones within tumors. In this perspective, we summarize the sources of intra-tumor phenotypic heterogeneity with emphasis on genetic heterogeneity. We review exptl. evidence for the existence of both intra-tumor clonal heterogeneity as well as frequent evolutionary divergence between primary tumors and metastatic outgrowths. Furthermore, we discuss potential biol. and clin. implications of intra-tumor clonal heterogeneity.
33. 33

    Ciccarese, C.; Massari, F.; Iacovelli, R.; Fiorentino, M.; Montironi, R.; Di Nunno, V.; Giunchi, F.; Brunelli, M.; Tortora, G. Prostate Cancer Heterogeneity: Discovering Novel Molecular Targets for Therapy. Cancer Treat. Rev. 2017, 54, 68– 73,  DOI: 10.1016/j.ctrv.2017.02.001

    Google Scholar

    There is no corresponding record for this reference.
34. 34

    Rybalov, M.; Ananias, H. J. K.; Hoving, H. D.; van der Poel, H. G.; Rosati, S.; de Jong, I. J. PSMA, EpCAM, VEGF and GRPR as Imaging Targets in Locally Recurrent Prostate Cancer after Radiotherapy. Int. J. Mol. Sci. 2014, 15 (4), 6046– 6061,  DOI: 10.3390/ijms15046046

    Google Scholar

    34

    PSMA, EpCAM, VEGF and GRPR as Imaging targets in locally recurrent prostate cancer after radiotherapy

    Rybalov, Maxim; Ananias, Hildo J. K.; Hoving, Hilde D.; van der Poel, Henk G.; Rosati, Stefano; de Jong, Igle J.

    International Journal of Molecular Sciences (2014), 15 (4), 6046-6061, 16CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)

    In this retrospective pilot study, the expression of the prostate-specific membrane antigen (PSMA), the epithelial cell adhesion mol. (EpCAM), the vascular endothelial growth factor (VEGF) and the gastrin-releasing peptide receptor (GRPR) in locally recurrent prostate cancer after brachytherapy or external beam radiotherapy (EBRT) was investigated, and their adequacy for targeted imaging was analyzed. Prostate cancer specimens were collected of 17 patients who underwent salvage prostatectomy because of locally recurrent prostate cancer after brachytherapy or EBRT. Immunohistochem. was performed. A pathologist scored the immunoreactivity in prostate cancer and stroma. Staining for PSMA was seen in 100% (17/17), EpCAM in 82.3% (14/17), VEGF in 82.3% (14/17) and GRPR in 100% (17/17) of prostate cancer specimens. Staining for PSMA, EpCAM and VEGF was seen in 0% (0/17) and for GRPR in 100% (17/17) of the specimens' stromal compartments. In 11.8% (2/17) of cases, the GRPR staining intensity of prostate cancer was higher than stroma, while in 88.2% (15/17), the staining was equal. Based on the absence of stromal staining, PSMA, EpCAM and VEGF show high tumor distinctiveness. Therefore, PSMA, EpCAM and VEGF can be used as targets for the bioimaging of recurrent prostate cancer after EBRT to exclude metastatic disease and/or to plan local salvage therapy.
35. 35

    Liolios, C.; Sachpekidis, C.; Schäfer, M.; Kopka, K. Bispecific Radioligands Targeting Prostate-Specific Membrane Antigen and Gastrin-Releasing Peptide Receptors on the Surface of Prostate Cancer Cells. J. Label. Compd. Radiopharm. 2019, 62 (8), 510– 522,  DOI: 10.1002/jlcr.3749

    Google Scholar

    There is no corresponding record for this reference.
36. 36

    Liolios, C. C.; Fragogeorgi, E. A.; Zikos, C.; Loudos, G.; Xanthopoulos, S.; Bouziotis, P.; Paravatou-Petsotas, M.; Livaniou, E.; Varvarigou, A. D.; Sivolapenko, G. B. Structural Modifications of ^99mTc-Labelled Bombesin-like Peptides for Optimizing Pharmacokinetics in Prostate Tumor Targeting. Int. J. Pharm. 2012, 430 (1–2), 1– 17,  DOI: 10.1016/j.ijpharm.2012.02.049

    Google Scholar

    There is no corresponding record for this reference.
37. 37

    Reubi, J. C.; Maecke, H. R. Approaches to Multireceptor Targeting: Hybrid Radioligands, Radioligand Cocktails, and Sequential Radioligand Applications. J. Nucl. Med. 2017, 58 (Supplement 2), 10S– 16S,  DOI: 10.2967/jnumed.116.186882

    Google Scholar

    37

    Approaches to multireceptor targeting: hybrid radioligands, radioligand cocktails, and sequential radioligand applications

    Reubi, Jean Claude; Maecke, Helmut R.

    Journal of Nuclear Medicine (2017), 58 (Suppl. 2), 10S-16SCODEN: JNMEAQ; ISSN:1535-5667. (Society of Nuclear Medicine and Molecular Imaging)

    Modern drug discovery highly depends on the identification and validation of the drug targets. Using the method of in vitro quant. receptor autoradiog., we demonstrated that-for instance, in neuroendocrine tumors-up to 3 receptors can be coexpressed at a relatively high d. In addn., nonendocrine tumors such as breast, prostate, and brain tumors concomitantly express several G protein-coupled receptors at a high d. We propose 3 strategies for exploiting these findings for multireceptor targeting in vivo: use of heterobivalent or heteromultivalent ligands, which may bind simultaneously or monovalently to their different mol. targets; coinjection of a cocktail of radioligands; and sequential injection of different radioligands. Any of these strategies may help to remedy some of the major problems in cancer targeting: heterogeneity, change in phenotype during disease progression, and resistance.
38. 38

    Handl, H. L.; Vagner, J.; Han, H.; Mash, E.; Hruby, V. J.; Gillies, R. J. Hitting Multiple Targets with Multimeric Ligands. Expert Opin. Ther. Targets 2004, 8 (6), 565– 586,  DOI: 10.1517/14728222.8.6.565

    Google Scholar

    38

    Hitting multiple targets with multimeric ligands

    Handl, Heather L.; Vagner, Josef; Han, Haiyong; Mash, Eugene; Hruby, Victor J.; Gillies, Robert J.

    Expert Opinion on Therapeutic Targets (2004), 8 (6), 565-586CODEN: EOTTAO; ISSN:1472-8222. (Ashley Publications Ltd.)

    A review. Multimeric ligands consist of multiple monomeric ligands attached to a single backbone mol., creating a multimer that can bind to multiple receptors or targets simultaneously. Numerous examples of multimeric binding exist within nature. Due to the multiple and simultaneous binding events, multimeric ligands bind with an increased affinity compared to their corresponding monomers. Multimeric ligands may provide opportunities in the field of drug discovery by providing enhanced selectivity and affinity of binding interactions, thus providing mol.-based targeted therapies. However, gaps in our knowledge currently exist regarding the quant. measures for important design characteristics, such as flexibility, length and orientation of the inter-ligand linkers, receptor d. and ligand sequence. In this review, multimeric ligand binding in two sep. phases is examd. The prerecruitment phase describes the binding of one ligand of a multimer to its corresponding receptor, an event similar to monomeric ligand binding. This results in transient increases in the local concn. of the other ligands, leading to apparent cooperativity. The postrecruitment phase only occurs once all receptors have been aligned and bound by their corresponding ligand. This phase is analogous to DNA-DNA interactions in that the stability of the complex is derived from phys. orientation. Multiple factors influence the kinetics and thermodn. of multimeric binding, and these are discussed.
39. 39

    Eder, M.; Schäfer, M.; Bauder-Wüst, U.; Haberkorn, U.; Eisenhut, M.; Kopka, K. Preclinical Evaluation of a Bispecific Low-Molecular Heterodimer Targeting Both PSMA and GRPR for Improved PET Imaging and Therapy of Prostate Cancer. Prostate 2014, 74 (6), 659– 668,  DOI: 10.1002/pros.22784

    Google Scholar

    There is no corresponding record for this reference.
40. 40

    Liolios, C.; Schäfer, M.; Haberkorn, U.; Eder, M.; Kopka, K. Novel Bispecific PSMA/GRPr Targeting Radioligands with Optimized Pharmacokinetics for Improved PET Imaging of Prostate Cancer. Bioconjugate Chem. 2016, 27 (3), 737– 751,  DOI: 10.1021/acs.bioconjchem.5b00687

    Google Scholar

    40

    Novel Bispecific PSMA/GRPr Targeting Radioligands with Optimized Pharmacokinetics for Improved PET Imaging of Prostate Cancer

    Liolios, C.; Schaefer, M.; Haberkorn, U.; Eder, M.; Kopka, K.

    Bioconjugate Chemistry (2016), 27 (3), 737-751CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)

    A new series of bispecific radioligands (BRLs) targeting prostate-specific membrane antigen (PSMA) and gastrin releasing peptide receptor (GRPr), both expressed on prostate cancer cells, was developed. Their design was based on the bombesin (BN) analog, H2N-PEG2-[D-Tyr6,β-Ala11,Thi13,Nle14]BN(6-14), which binds to GRPr with high affinity and specificity, and the peptidomimetic urea-based pseudoirreversible inhibitor of PSMA, Glu-ureido-Lys. The two pharmacophores were coupled through copper(I)-catalyzed azide-alkyne cycloaddn. to the bis(tetrafluorophenyl) ester of the chelating agent HBED-CC via amino acid linkers made of pos. charged His (H) and neg. charged Glu (E): -(HE)n- (n = 0-3). The BRLs were labeled with 68Ga, and their preliminary pharmacol. properties were evaluated in vitro (competitive and time kinetic binding assays) on prostate cancer (PC-3, LNCaP) and rat pancreatic (AR42J) cell lines and in vivo by biodistribution and small animal PET imaging studies in both normal and tumor-bearing mice. The IC50/Ki values detd. for all BRLs essentially matched those of the resp. monomers. The maximal cellular uptake of the BLRs was obsd. between 20 and 30 min. The BRLs showed a synergistic ability in vivo by targeting both PSMA (LNCaP) and GRPr (PC-3) pos. tumors, whereas the charged -(HE)n- (n = 1-3) linkers significantly reduced the kidney and spleen uptake. The bispecific (PSMA and GRPr) targeting ability and optimized pharmacokinetics of the compds. developed in this study could lead to their future application in clin. practice as more sensitive radiotracers for noninvasive imaging of prostate cancer (PCa) by PET/CT and PET/MRI.
41. 41

    Mitran, B.; Varasteh, Z.; Abouzayed, A.; Rinne, S. S.; Puuvuori, E.; De Rosa, M.; Larhed, M.; Tolmachev, V.; Orlova, A.; Rosenström, U. Bispecific GRPR-Antagonistic Anti-PSMA/GRPR Heterodimer for PET and SPECT Diagnostic Imaging of Prostate Cancer. Cancers (Basel) 2019, 11 (9), 1371,  DOI: 10.3390/cancers11091371

    Google Scholar

    There is no corresponding record for this reference.
42. 42

    Lundmark, F.; Abouzayed, A.; Mitran, B.; Rinne, S. S.; Varasteh, Z.; Larhed, M.; Tolmachev, V.; Rosenström, U.; Orlova, A. Heterodimeric Radiotracer Targeting PSMA and GRPR for Imaging of Prostate Cancer─Optimization of the Affinity towards PSMA by Linker Modification in Murine Model. Pharmaceutics 2020, 12 (7), 614,  DOI: 10.3390/pharmaceutics12070614

    Google Scholar

    There is no corresponding record for this reference.
43. 43

    Mendoza-Figueroa, M. J.; Escudero-Castellanos, A.; Ramirez-Nava, G. J.; Ocampo-García, B. E.; Santos-Cuevas, C. L.; Ferro-Flores, G.; Pedraza-Lopez, M.; Avila-Rodriguez, M. A. Preparation and Preclinical Evaluation of ⁶⁸Ga-IPSMA-BN as a Potential Heterodimeric Radiotracer for PET-Imaging of Prostate Cancer. J. Radioanal. Nucl. Chem. 2018, 318 (3), 2097– 2105,  DOI: 10.1007/s10967-018-6285-3

    Google Scholar

    There is no corresponding record for this reference.
44. 44

    Bandari, R. P.; Carmack, T. L.; Malhotra, A.; Watkinson, L.; Fergason Cantrell, E. A.; Lewis, M. R.; Smith, C. J. Development of Heterobivalent Theranostic Probes Having High Affinity/Selectivity for the GRPR/PSMA. J. Med. Chem. 2021, 64 (4), 2151– 2166,  DOI: 10.1021/acs.jmedchem.0c01785

    Google Scholar

    There is no corresponding record for this reference.
45. 45

    Yan, Y.; Chen, X. Peptide Heterodimers for Molecular Imaging. Amino Acids 2011, 41, 1081– 1092,  DOI: 10.1007/s00726-010-0546-y

    Google Scholar

    45

    Peptide heterodimers for molecular imaging

    Yan, Yongjun; Chen, Xiaoyuan

    Amino Acids (2011), 41 (5), 1081-1092CODEN: AACIE6; ISSN:0939-4451. (SpringerWienNewYork)

    A review. One main issue with peptide-based mol. imaging probes is their relatively low tumor affinity and short retention time. To improve peptide binding affinity, multivalency approach has been introduced. Traditionally, this approach involves the use of peptide homodimers or homomultimers in which peptide ligands of the same type are constructed with suitable linkers. Recently, a new approach using peptide heterodimers has emerged as a promising method for targeting multi-receptor over-expressed tumor cells. Significant affinity enhancements have been obsd. with peptide heterodimers compared with their parent peptide monomers. In a peptide heterodimer, two different peptide ligands capable of targeting two different receptors are covalently linked. The binding modes of peptide heterodimers can be monovalent or bivalent depending on whether simultaneous binding of two ligands can be achieved. Increased local ligand concn. and improved binding kinetics contribute to enhanced binding in both monovalent- and bivalent binding modes, while multivalency effect also plays an important role in bivalent binding mode. As many tumors overexpress multiple receptors, more peptide heterodimer-based mol. imaging probes are expected to be developed in future. This review article will discuss the peptide homodimers and heterodimers for mol. imaging with special emphasis on peptide heterodimers.
46. 46

    Cheng, C.; Pan, L.; Dimitrakopoulou-Strauss, A.; Schäfer, M.; Wängler, C.; Wängler, B.; Haberkorn, U.; Strauss, L. G. Comparison between ⁶⁸Ga-Bombesin (⁶⁸Ga-BZH3) and the CRGD Tetramer ⁶⁸Ga-RGD4 Studies in an Experimental Nude Rat Model with a Neuroendocrine Pancreatic Tumor Cell Line. EJNMMI Res. 2011, 1, 34,  DOI: 10.1186/2191-219X-1-34

    Google Scholar

    46

    Comparison between 68Ga-bombesin (68Ga-BZH3) and the cRGD tetramer 68Ga-RGD4 studies in an experimental nude rat model with a neuroendocrine pancreatic tumor cell line

    Cheng Caixia; Pan Leyun; Dimitrakopoulou-Strauss Antonia; Schafer Martin; Wangler Carmen; Wangler Bjorn; Haberkorn Uwe; Strauss Ludwig G

    EJNMMI research (2011), 1 (), 34 ISSN:.

    OBJECTIVES: Receptor scintigraphy gains more interest for diagnosis and treatment of tumors, in particular for neuroendocrine tumors (NET). We used a pan-Bombesin analog, the peptide DOTA-PEG2-[D-tyr6, β-Ala11, Thi13, Nle14] BN(6-14) amide (BZH3). BZH3 binds to at least three receptor subtypes: the BB1 (Neuromedin B), BB2 (Gastrin-releasing peptide, GRP), and BB3. Imaging of ανβ3 integrin expression playing an important role in angiogenesis and metastasis was accomplished with a 68Ga-RGD tetramer. The purpose of this study was to investigate the kinetics and to compare both tracers in an experimental NET cell line. METHODS: This study comprised nine nude rats inoculated with the pancreatic tumor cell line AR42J. Dynamic positron emission tomography (PET) scans using 68Ga-BZH3 and 68Ga-RGD tetramer were performed (68Ga-RGD tetramer: n = 4, 68Ga-BZH3: n = 5). Standardized uptake values (SUVs) were calculated, and a two-tissue compartmental learning-machine model (calculation of K1 - k4 vessel density (VB) and receptor binding potential (RBP)) as well as a non-compartmental model based on the fractal dimension was used for quantitative analysis of both tracers. Multivariate analysis was used to evaluate the kinetic data. RESULTS: The PET kinetic parameters showed significant differences when individual parameters were compared between groups. Significant differences were found in FD, VB, K1, and RBP (p = 0.0275, 0.05, 0.05, and 0.0275 respectively). The 56- to 60-min SUV for 68Ga-BZH3, with a range of 0.86 to 1.29 (median, 1.19) was higher than the corresponding value for the 68Ga-RGD tetramer, with a range of 0.78 to 1.31 (median, 0.99). Furthermore, FD, VB, K1, and RBP for 68Ga-BZH3 were generally higher than the corresponding values for the 68Ga-RGD tetramer, whereas k3 was slightly higher for 68Ga-RGD tetramer. CONCLUSIONS: As a parameter that reflects receptor binding, the increase of K1 for 68Ga-BZH3 indicated higher expression of bombesin receptors than that of the ανβ3 integrin in neuroendocrine tumors. 68Ga-BZH3 seems better suited for diagnosis of NETs owing to higher global tracer uptake.
47. 47

    Strauss, L. G.; Koczan, D.; Seiz, M.; Tuettenberg, J.; Schmieder, K.; Pan, L.; Cheng, C.; Dimitrakopoulou-Strauss, A. Correlation of the Ga-68-Bombesin Analog Ga-68-BZH3 with Receptors Expression in Gliomas as Measured by Quantitative Dynamic Positron Emission Tomography (DPET) and Gene Arrays. Mol. Imaging Biol. 2012, 14 (3), 376– 383,  DOI: 10.1007/s11307-011-0508-0

    Google Scholar

    47

    Correlation of the Ga-68-bombesin analog Ga-68-BZH3 with receptors expression in gliomas as measured by quantitative dynamic positron emission tomography (dPET) and gene arrays

    Strauss Ludwig G; Koczan Dirk; Seiz Marcel; Tuettenberg Jochen; Schmieder Kirsten; Pan Leyun; Cheng Caixia; Dimitrakopoulou-Strauss Antonia

    Molecular imaging and biology (2012), 14 (3), 376-83 ISSN:.

    PURPOSE: The kinetics of Ga-68-BZH3, a Ga-68-bombesin analog, was compared to molecular biological data obtained from gene arrays in seven patients with a recurrent glioma. The primary aim of this study was the correlation of receptor expression and tracer kinetics. PROCEDURES: Dynamic positron emission tomography studies were performed and the data were analyzed by a volume-of-interest technique using a two-tissue compartment model as well as a non-compartment model. Gene array data were obtained from gene array analysis of tumor tissue samples. RESULTS: The correlation analysis revealed a significant nonlinear correlation of r = 0.89 (p < 0.03) for k1 and BB(2) (gastrin-releasing peptide receptor). BB(1) and BB(3) were not significantly correlated with k1. vb and k3 were not significantly correlated with the expression data of the receptors on the p < 0.05 level. CONCLUSIONS: The parameter k1 is correlated with the expression of BB(2) based on gene array data. The quantitative analysis of the Ga-68-BZH3 kinetics can be used to predict the receptor expression of BB(2) in gliomas based on k1 of the compartment analysis. However, this study is limited to the expression data on the mRNA level and further studies are needed to assess the correlation of gene expression on the protein level.
48. 48

    Escudero-Castellanos, A.; Ocampo-García, B.; Ferro-Flores, G.; Santos-Cuevas, C.; Morales-Ávila, E.; Luna-Gutiérrez, M.; Isaac-Olivé, K. Synthesis and Preclinical Evaluation of the ¹⁷⁷Lu-DOTA-PSMA(Inhibitor)-Lys 3 -Bombesin Heterodimer Designed as a Radiotheranostic Probe for Prostate Cancer. Nucl. Med. Commun. 2019, 40 (3), 278– 286,  DOI: 10.1097/MNM.0000000000000966

    Google Scholar

    There is no corresponding record for this reference.
49. 49

    Santos-Cuevas, C.; Ferro-Flores, G.; García-Pérez, F. O.; Jiménez-Mancilla, N.; Ramírez-Nava, G.; Ocampo-García, B.; Luna-Gutiérrez, M.; Azorín-Vega, E.; Davanzo, J.; Soldevilla-Gallardo, I. ¹⁷⁷Lu-DOTA-HYNIC-Lys(Nal)-Urea-Glu: Biokinetics, Dosimetry, and Evaluation in Patients with Advanced Prostate Cancer. Contrast Media Mol. Imaging 2018, 2018, 1– 10,  DOI: 10.1155/2018/5247153

    Google Scholar

    There is no corresponding record for this reference.
50. 50

    Abouzayed, A.; Yim, C.-B.; Mitran, B.; Rinne, S. S.; Tolmachev, V.; Larhed, M.; Rosenström, U.; Orlova, A. Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer. Pharmaceutics 2019, 11 (7), 358,  DOI: 10.3390/pharmaceutics11070358

    Google Scholar

    There is no corresponding record for this reference.
51. 51

    Eltit, F.; Robinson, N.; Yu, P. L. I.; Pandey, M.; Lozada, J.; Guo, Y.; Sharma, M.; Ozturan, D.; Ganier, L.; Belanger, E.; Lack, N. A.; Perrin, D. M.; Cox, M. E.; Goldenberg, S. L. The “Ins and Outs” of Prostate Specific Membrane Antigen (PSMA) as Specific Target in Prostate Cancer Therapy. Adv. Exp. Med. Biol. 2023, 1408, 291– 308,  DOI: 10.1007/978-3-031-26163-3_16

    Google Scholar

    There is no corresponding record for this reference.
52. 52

    Lundmark, F.; Abouzayed, A.; Rinne, S. S.; Timofeev, V.; Sipkina, N.; Naan, M.; Kirichenko, A.; Vasyutina, M.; Ryzhkova, D.; Tolmachev, V.; Rosenström, U.; Orlova, A. Preclinical Characterisation of PSMA/GRPR-Targeting Heterodimer [68Ga]Ga-BQ7812 for PET Diagnostic Imaging of Prostate Cancer: A Step towards Clinical Translation. Cancers (Basel) 2023, 15 (2), 442,  DOI: 10.3390/cancers15020442

    Google Scholar

    There is no corresponding record for this reference.
53. 53

    Liolios, C.; Buchmuller, B.; Bauder-Wüst, U.; Schäfer, M.; Leotta, K.; Haberkorn, U.; Eder, M.; Kopka, K. Monomeric and Dimeric ⁶⁸ Ga-Labeled Bombesin Analogues for Positron Emission Tomography (PET) Imaging of Tumors Expressing Gastrin-Releasing Peptide Receptors (GRPrs). J. Med. Chem. 2018, 61 (5), 2062– 2074,  DOI: 10.1021/acs.jmedchem.7b01856

    Google Scholar

    There is no corresponding record for this reference.
54. 54

    Salvanou, E. A.; Kolokithas-Ntoukas, A.; Liolios, C.; Xanthopoulos, S.; Paravatou-Petsotas, M.; Tsoukalas, C.; Avgoustakis, K.; Bouziotis, P. Preliminary Evaluation of Iron Oxide Nanoparticles Radiolabeled with 68Ga and 177Lu as Potential Theranostic Agents. Nanomater. 2022, Vol. 12, Page 2490 2022, 12 (14), 2490,  DOI: 10.3390/nano12142490

    Google Scholar

    There is no corresponding record for this reference.
55. 55

    Barinka, C.; Hlouchova, K.; Rovenska, M.; Majer, P.; Dauter, M.; Hin, N.; Ko, Y.-S.; Tsukamoto, T.; Slusher, B. S.; Konvalinka, J.; Lubkowski, J. Structural Basis of Interactions between Human Glutamate Carboxypeptidase II and Its Substrate Analogs. J. Mol. Biol. 2008, 376 (5), 1438– 1450,  DOI: 10.1016/j.jmb.2007.12.066

    Google Scholar

    There is no corresponding record for this reference.
56. 56

    Barinka, C.; Byun, Y.; Dusich, C. L.; Banerjee, S. R.; Chen, Y.; Castanares, M.; Kozikowski, A. P.; Mease, R. C.; Pomper, M. G.; Lubkowski, J. Interactions between Human Glutamate Carboxypeptidase II and Urea-Based Inhibitors: Structural Characterization. J. Med. Chem. 2008, 51 (24), 7737– 7743,  DOI: 10.1021/jm800765e

    Google Scholar

    56

    Interactions between Human Glutamate Carboxypeptidase II and Urea-Based Inhibitors: Structural Characterization

    Barinka, Cyril; Byun, Youngjoo; Dusich, Crystal L.; Banerjee, Sangeeta R.; Chen, Ying; Castanares, Mark; Kozikowski, Alan P.; Mease, Ronnie C.; Pomper, Martin G.; Lubkowski, Jacek

    Journal of Medicinal Chemistry (2008), 51 (24), 7737-7743CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    Urea-based, low mol. wt. ligands of glutamate carboxypeptidase II (GCPII) have demonstrated efficacy in various models of neurol. disorders and can serve as imaging agents for prostate cancer. To enhance further development of such compds., we detd. x-ray structures of four complexes between human GCPII and urea-based inhibitors at high resoln. All ligands demonstrate an invariant glutarate moiety within the S1' pocket of the enzyme. The ureido linkage between P1 and P1' inhibitor sites interacts with the active-site Zn12+ ion and the side chains of Tyr-552 and His-553. Interactions within the S1 pocket are defined primarily by a network of hydrogen bonds between the P1 carboxylate group of the inhibitors and the side chains of Arg-534, Arg-536, and Asn-519. Importantly, we have identified a hydrophobic pocket accessory to the S1 site that can be exploited for structure-based design of novel GCPII inhibitors with increased lipophilicity.
57. 57

    Peng, S.; Zhan, Y.; Zhang, D.; Ren, L.; Chen, A.; Chen, Z. F.; Zhang, H. Structures of Human Gastrin-Releasing Peptide Receptors Bound to Antagonist and Agonist for Cancer and Itch Therapy. Proc. Natl. Acad. Sci. U. S. A. 2023, 120 (6), e2216230120,  DOI: 10.1073/pnas.2216230120

    Google Scholar

    There is no corresponding record for this reference.
58. 58

    McDevitt, M. R.; Barendswaard, E.; Ma, D.; Lai, L.; Curcio, M. J.; Sgouros, G.; Ballangrud, A. M.; Yang, W.-H.; Finn, R. D.; Pellegrini, V.; Geerlings, M. W., Jr.; Lee, M.; Brechbiel, M. W.; Bander, N. H.; Cordon-Cardo, C.; Scheinberg, D. A. An {{alpha}}-Particle Emitting Antibody ([213 Bi]J591) for Radioimmunotherapy of Prostate Cancer. Cancer Res. 2000, 60 (21), 6095– 6100

    Google Scholar

    There is no corresponding record for this reference.
59. 59

    Wang, X.; Ma, D.; Olson, W. C.; Heston, W. D. W. In Vitro and in Vivo Responses of Advanced Prostate Tumors to PSMA ADC, an Auristatin-Conjugated Antibody to Prostate-Specific Membrane Antigen. Mol. Cancer Ther. 2011, 10 (9), 1728– 1739,  DOI: 10.1158/1535-7163.MCT-11-0191

    Google Scholar

    59

    In Vitro and In Vivo Responses of Advanced Prostate Tumors to PSMA ADC, an Auristatin-Conjugated Antibody to Prostate-Specific Membrane Antigen

    Wang, Xinning; Ma, Dangshe; Olson, William C.; Heston, Warren D. W.

    Molecular Cancer Therapeutics (2011), 10 (9), 1728-1739CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)

    Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for therapy. PSMA ADC is an antibody-drug conjugate (ADC) that consists of a fully human anti-PSMA monoclonal antibody conjugated to monomethylauristatin E through a valine-citrulline linker. In this study, the antitumor activity of PSMA ADC was evaluated against a panel of prostate cancer cell lines in vitro and in a novel in vivo model of taxane-refractory human prostate cancer. In vitro cell killing was efficient for cells with abundant PSMA expression (>105 mols./cell; IC50 ≤ 0.022 nmol/L) and 1000-fold less efficient for cells with undetectable PSMA (IC50 > 30 nmol/L). Intermediate potency (IC50 = 0.80 nmol/L) was obsd. for cells with approx. 104 mols. of PSMA per cell, indicating a threshold PSMA level for selective cell killing. Similar in vitro activity was obsd. against androgen-dependent and -independent cells that had abundant PSMA expression. In vitro activity of PSMA ADC was also dependent on internalization and proper N-glycosylation/folding of PSMA. In contrast, less potent and nonselective cytotoxic activity was obsd. for a control ADC, free monomethylauristatin E, and other microtubule inhibitors. PSMA ADC showed high in vivo activity in treating xenograft tumors that had progressed following an initial course of docetaxel therapy, including tumors that were large (>700 mm3) before treatment with PSMA ADC. This study defines determinants of antitumor activity of a novel ADC. The findings here support the clin. evaluation of this agent in advanced prostate cancer. Mol Cancer Ther; 10(9); 1728-39.
60. 60

    Schuhmacher, J.; Zhang, H.; Doll, J.; Mäcke, H. R.; Matys, R.; Hauser, H.; Henze, M.; Haberkorn, U.; Eisenhut, M. GRP Receptor-Targeted PET of a Rat Pancreas Carcinoma Xenograft in Nude Mice with a ⁶⁸Ga-Labeled Bombesin(6–14) Analog. J. Nucl. Med. 2005, 46 (4), 691– 699

    Google Scholar

    There is no corresponding record for this reference.