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
Autor: | Zongrun Jiang, Tammy L. Rold, Rajendra P. Bandari, Daniel L. Kirkpatrick, Gary L. Sieckman, Kurt J. Bassuner, Timothy J. Hoffman, Tamila Stott Reynolds, Charles J. Smith, Ashley F. Szczodroski, James P. Connors, Nicole Bernskoetter |
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Rok vydání: | 2014 |
Předmět: |
Glutamate Carboxypeptidase II
Male Cancer Research Peptide Chemistry Techniques Synthetic Acetates Article Glutarates Heterocyclic Compounds 1-Ring Mice chemistry.chemical_compound Cell Line Tumor Gastrin-releasing peptide LNCaP Biomarkers Tumor Peptide synthesis Glutamate carboxypeptidase II Radioligand Animals Humans Urea Radiology Nuclear Medicine and imaging chemistry.chemical_classification Radiochemistry Prostatic Neoplasms Bombesin Biological Transport Ligand (biochemistry) Molecular biology Receptors Bombesin Amino Acids Neutral Copper Radioisotopes chemistry Biochemistry Positron-Emission Tomography Aminocaproic Acid Antigens Surface Molecular Medicine Female Protein Binding |
Zdroj: | Nuclear Medicine and Biology. 41:355-363 |
ISSN: | 0969-8051 |
Popis: | 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-( 64 Cu-NODAGA)-5-Ava-BBN(7-14)NH 2 ] 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)NH 2 =bombesin, a GRPr-specific peptide targeting probe. Methods The PSMA/GRPr dual targeting ligand precursor [DUPA-6-Ahx-K-5-Ava-BBN(7-14)NH 2 ], was synthesized by solid-phase and manual peptide synthesis, after which NODAGA was added via manual conjugation to the e-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 64 CuCl 2 and nat CuCl 2 . 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 18h post-injection (p.i.). Results Competitive binding assays in PC-3 and LNCaP cells indicated high receptor binding affinity for the [DUPA-6-Ahx-( nat Cu-NODAGA)-5-Ava-BBN(7-14)NH 2 ] conjugate. MicroPET scintigraphy in PC-3/LNCaP tumor-bearing mice indicated that xenografted tumors were visible at 18h p.i. with collateral, background radiation also being observed in non-target tissue. Conclusions DUPA-6-Ahx-( 64 Cu-NODAGA)-5-Ava-BBN(7-14)NH 2 ] 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-( 64 Cu-NODAGA)-5-Ava-BBN(7-14)NH 2 in tumor-bearing mice indicate that further studies are necessary to optimize uptake and retention of tracer in GRPr- and PSMA-positive tissues. |
Databáze: | OpenAIRE |
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