Development of Heterobivalent Theranostic Probes Having High Affinity/Selectivity for the GRPR/PSMA

• Published in: Journal of medicinal chemistry Vol. 64; no. 4; pp. 2151 - 2166
• Main Authors: Bandari, Rajendra P, Carmack, Terry L, Malhotra, Anil, Watkinson, Lisa, Fergason Cantrell, Emily A, Lewis, Michael R, Smith, Charles J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.02.2021; Amer Chemical Soc
• Subjects: Animals; Antigens, Surface - metabolism; Cell Line, Tumor; Chemistry, Medicinal; Coordination Complexes - pharmacokinetics; Coordination Complexes - pharmacology; Fluorescent Dyes - pharmacokinetics; Fluorescent Dyes - pharmacology; Glutamate Carboxypeptidase II - metabolism; Humans; Indium Radioisotopes - chemistry; Life Sciences & Biomedicine; Lutetium - chemistry; Male; Membrane Glycoproteins - metabolism; Mice; Oligopeptides - pharmacokinetics; Oligopeptides - pharmacology; Pharmacology & Pharmacy; Precision Medicine - methods; Radioisotopes - chemistry; Radiopharmaceuticals - pharmacokinetics; Radiopharmaceuticals - pharmacology; Receptors, Bombesin - metabolism; Science & Technology; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; TARGETING VECTOR; MEMBRANE ANTIGEN; PHARMACOKINETICS; GRP-R AGONIST; BOMBESIN ANALOGS; PROSTATE-CANCER PATIENTS; SYSTEMIC RADIOTHERAPY; LU-177-AMBA; PRECLINICAL EVALUATION; PET
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01785

In this study, we describe the development of heterobivalent [DUPA-6-Ahx-([111In]­In-DO3A)-8-Aoc-BBN ANT] and [DUPA-6-Ahx-([177Lu]­Lu-DO3A)-8-Aoc-BBN ANT] radiotracers that display very high selectivity/specificity for gastrin-releasing peptide receptor (GRPR)-/prostate-specific membrane antigen (PSMA)-expressing cells. These studies include metallation, purification, characterization, and in vitro and in vivo evaluation of the new small-molecule-/peptide-based radiopharmaceuticals having utility for imaging and potentially therapy. Competitive displacement binding assays using PC-3 cells and LNCaP cell membranes showed high binding affinity for the GRPR or the PSMA. Biodistribution studies showed favorable excretion pharmacokinetics with high tumor uptake in PC-3 or PC-3 prostatic inhibin peptide (PIP) tumor-bearing mice. For example, tumor accumulation at the 1 h time point ranged from (4.74 ± 0.90) to (7.51 ± 2.61)%ID/g. Micro-single-photon emission computed tomography (microSPECT) molecular imaging investigations showed very high uptake in tumors with minimal accumulation of tracers in the surrounding collateral tissues in xenografted mice at 4 h postintravenous injection. In conclusion, [DUPA-6-Ahx-([111In]­In-DO3A)-8-Aoc-BBN ANT] and [DUPA-6-Ahx-([177Lu]­Lu-DO3A)-8-Aoc-BBN ANT] tracers displayed favorable pharmacokinetic and excretion profiles with high uptake and retention in tumors.