Synthesis and biological evaluation of copper-64 radiolabeled [DUPA-6-Ahx-(NODAGA)-5-Ava-BBN(7-14)NH2], a novel bivalent targeting vector having affinity for two distinct biomarkers (GRPr/PSMA) of prostate cancer |
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| Affiliation: | 1. Research Service, Truman VA, Columbia, MO 65201, USA;2. Department of Radiology, University of Missouri School of Medicine, Columbia, MO 65211, USA;3. University of Missouri Research Reactor Center, University of Missouri, Columbia, MO 65211, USA;4. Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 65211, USA;5. Department of Chemistry, University of Missouri, Columbia, MO 65211, USA;6. Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO 65211, USA;1. Preclinical PET Platform, Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden;2. Department of Immunology, Genetics and Pathology, Faculty of Medicine, Uppsala University, Uppsala, Sweden;3. Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden;4. Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden;5. Science for Life Laboratory, Department of Medicinal Chemistry, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden;1. Division of Radiological Chemistry, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland;2. Department of Nuclear Medicine, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany;3. Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Murtenstrasse 31, CH-3010 Berne, Switzerland;1. Radioisotope Research Division, Department of Research Reactor Utilization, Korea Atomic Energy Research Institute, Daejeon 305-353, Republic of Korea;2. Bio-therapy Human Resources Center, Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Korea |
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| Abstract: | Gastrin-releasing peptide receptors (GRPr) and prostate-specific membrane antigen (PSMA) are two identifying biomarkers expressed in very high numbers on prostate cancer cells and could serve as a useful tool for molecular targeting and diagnosis of disease via positron-emission tomography (PET). The aim of this study was to produce the multipurpose, bivalent [DUPA-6-Ahx-(64Cu-NODAGA)-5-Ava-BBN(7-14)NH2] radioligand for prostate cancer imaging, where DUPA = (2-[3-(1,3-dicarboxypropyl)-ureido]pentanedioic acid), a small-molecule, PSMA-targeting probe, 6Ahx = 6-aminohexanoic acid, 5-Ava = 5-aminovaleric acid, NODAGA = [2-(4,7-biscarboxymethyl)-1,4,7-(triazonan-1-yl)pentanedioic acid] (a derivative of NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid)), and BBN(7-14)NH2 = bombesin, a GRPr-specific peptide targeting probe.MethodsThe PSMA/GRPr dual targeting ligand precursor [DUPA-6-Ahx-K-5-Ava-BBN(7-14)NH2], was synthesized by solid-phase and manual peptide synthesis, after which NODAGA was added via manual conjugation to the ε-amine of lysine (K). The new bivalent GRPr/PSMA targeting vector was purified by reversed-phase high performance liquid chromatography (RP-HPLC), characterized by electrospray-ionization mass spectrometry (ESI-MS), and metallated with 64CuCl2 and natCuCl2. The receptor binding affinity was evaluated in human, prostate, PC-3 (GRPr-positive) and LNCaP (PSMA-positive) cells and the tumor-targeting efficacy determined in severe combined immunodeficient (SCID) and athymic nude mice bearing PC-3 and LNCaP tumors. Whole-body maximum intensity microPET/CT images of PC-3/LNCaP tumor-bearing mice were obtained 18 h post-injection (p.i.).ResultsCompetitive binding assays in PC-3 and LNCaP cells indicated high receptor binding affinity for the [DUPA-6-Ahx-(natCu-NODAGA)-5-Ava-BBN(7-14)NH2] conjugate. MicroPET scintigraphy in PC-3/LNCaP tumor-bearing mice indicated that xenografted tumors were visible at 18 h p.i. with collateral, background radiation also being observed in non-target tissue.ConclusionsDUPA-6-Ahx-(64Cu-NODAGA)-5-Ava-BBN(7-14)NH2] targeting vector, as described herein, is the first example of a dual GRPr-/PSMA-targeting radioligand for molecular of imaging prostate tumors. Detailed in vitro studies and microPET molecular imaging investigations of [DUPA-6-Ahx-(64Cu-NODAGA)-5-Ava-BBN(7-14)NH2 in tumor-bearing mice indicate that further studies are necessary to optimize uptake and retention of tracer in GRPr- and PSMA-positive tissues. |
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