We
report herein the preclinical evaluation of new [64Cu]Cu-gastrin-releasing
peptide receptor (GRPR)-targeting tracers,
employing the potent peptide antagonist DPhe-Gln-Trp-Ala-VaI-Gly-His-Sta-Leu-NH2 conjugated to NOTA (in 1) or NODAGA (in 2) chelators via a 6-aminohexanoic acid linker. The Cu-1/2 metalated peptides were synthesized by reacting 1/2 with CuCl2 and were characterized
by LC-ESI-MS and HR-ESI-MS. Cu-1/2 exhibited
high GRPR-binding affinities with IC50 values <3 nM,
as measured in a competition assay using the GRPR-expressing human
PC-3 prostate cancer cell line and [125I]I-Tyr4-BBN as the competing ligand. Tracers [64Cu]Cu-1/2 were prepared in quantitative radiochemical yield
(by radio-HPLC), and their identities were confirmed by coelution
with their Cu-1/2 standards via comparative
HPLC studies. Lipophilicity was measured in 1-octanol/PBS (pH 7.4),
and the negative log D
7.4 values (≤−1)
confirmed the anticipated hydrophilic character for [64Cu]Cu-1/2. Both tracers demonstrated excellent in vitro stability, with ≥98% remaining intact through
24 h at physiological conditions (PBS, pH 7.4, 37 °C). Biodistribution
in PC-3 tumor-bearing mice demonstrated good tumor uptake (%ID/g at
4 h: 4.34 ± 0.71 for [64Cu]Cu-1, 3.92
± 1.03 for [64Cu]Cu-2) and rapid renal
clearance (≥87% ID at 4 h). Tumor uptake was receptor-mediated,
as verified by parallel GRPR-blocking studies. Small-animal PET/CT
imaging studies validated the biodistribution data. These preclinical
data support that the [64Cu]Cu-1/2 tracers show promise for further development as diagnostic PET imaging
agents of GRPR-expressing tumors.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.