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

Abstract

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.

• Authors: Rajendra P Bandari, Terry L Carmack, Anil Malhotra, Lisa Watkinson, Emily A Fergason Cantrell, Michael R Lewis, Charles J Smith
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 4 Pg. 2151-2166 (02 25 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 33534560 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antigens, Surface
• Coordination Complexes
• Fluorescent Dyes
• Indium Radioisotopes
• Membrane Glycoproteins
• Oligopeptides
• Radioisotopes
• Radiopharmaceuticals
• Receptors, Bombesin
• Lutetium
• Lutetium-177
• Indium-111
• FOLH1 protein, human
• Glutamate Carboxypeptidase II
• PSMA protein, mouse

Topics

• Animals
• Antigens, Surface (metabolism)
• Cell Line, Tumor
• Coordination Complexes (pharmacokinetics, pharmacology)
• Fluorescent Dyes (pharmacokinetics, pharmacology)
• Glutamate Carboxypeptidase II (metabolism)
• Humans
• Indium Radioisotopes (chemistry)
• Lutetium (chemistry)
• Male
• Membrane Glycoproteins (metabolism)
• Mice
• Oligopeptides (pharmacokinetics, pharmacology)
• Precision Medicine (methods)
• Radioisotopes (chemistry)
• Radiopharmaceuticals (pharmacokinetics, pharmacology)
• Receptors, Bombesin (metabolism)
• Tissue Distribution
• Tomography, Emission-Computed, Single-Photon