Impact of dianionic and dicationic linkers on tumor uptake and biodistribution of [ 64 64 Cu]Cu/NOTA peptide‐based gastrin‐releasing peptide receptors antagonists

摘要

In this study, we investigated for the first time the influence of 2‐aminoethyl‐piperazine‐1‐carboxylic acid (APCA) and amino‐hexanedioic‐1‐acid (AHDA) on tumor uptake and elimination kinetics of [ 64 Cu]‐radiolabeled gastrin releasing peptide receptors (GRPR) antagonists. Three GRPR antagonists containing the RM26 sequence were synthesized and conjugated with NOTA via different linkers (LK): polyethylene glycol (PEG–neutral), APCA (dicationic) or AHDA (dianionic). The NOTA‐LK‐RM26 peptides were radiolabeled with 64 Cu to assess their pharmacokinetic and positron emission tomography (PET) imaging properties using PC3 tumor‐bearing athymic nude mice. The inhibition constants (K i ) of the 3 nat Cu/NOTA‐LK‐RM26 peptides bearing PEG, dicationic and dianionic linkers were 0.98?±?0.48?nM, 0.95?±?0.21?nM, and 17.97?±?2.79?nM, respectively. The [ 64 Cu] NOTA‐LK‐RM26 conjugates were prepared with labeling yields superior to 95% and specific activities of 67 to 77?TBq/mmol. The 3 radiopeptides were stable in vivo and showed GRPR‐specific uptake in pancreas with a very fast washout of this tissue observed for [ 64 Cu]‐NOTA‐AHDA‐RM26 peptide. Results from imaging studies displayed specific PC3 tumor uptake for both [ 64 Cu]‐NOTA‐APCA‐ and AHDA‐RM26, similar kidney elimination and fast liver washout. Considering their adequate imaging characteristics, [ 64 Cu]‐NOTA‐LK‐RM26 bearing APCA‐ and AHDA‐linkers are promising candidates for GRPR‐targeted PET imaging prostate cancer.