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

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.