Abstract
This study evaluates the potential of a (177)Lu-labeled GRPR-targeting antagonist as a radiotherapeutic agent for tumors expressing the gastrin-releasing peptide receptor (GRPR). The therapeutic effect of the radioligand was investigated both as a monotherapy and in combination with the mTOR inhibitor everolimus. The GRPR antagonist, LF1 (AAZTA(5)-Pip-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH(2)), was synthesized using the chelator AAZTA(5) linked via a 4-amino-1-carboxymethylpiperidine (Pip) spacer and radiolabeled with lutetium-177. The preclinical evaluation included assessments of binding kinetics, blood and organ clearance, plasma protein binding, and metabolic stability. SPECT/CT imaging and biodistribution studies were performed in mice bearing PC3 xenograft tumors. To assess its therapeutic efficacy, PC-3-mice were treated with [(177)Lu]-Lu-LF1 either alone or following everolimus pretreatment. [(177)Lu]-Lu-LF1 showed high binding affinity (K(d) = 0.12 ± 0.01 nM) and favorable pharmacokinetics, including rapid blood clearance and low plasma protein binding (2-3% at 5 and 15 min p.i.). Although subject to enzymatic degradation, the radioligand demonstrated high, sustained, and specific tumor uptake (42 ± 5.0% IA/g at 1 h and 3.9 ± 1.1% IA/g at 144 h p.i.). Pancreatic uptake cleared quickly, allowing for high-contrast SPECT/CT imaging. Therapeutically, tumors treated with 93 MBq of [(177)Lu]-Lu-LF1 grew more slowly than those treated with 41 MBq. The combination of everolimus and [(177)Lu]-Lu-LF1 resulted in significant tumor growth inhibition, compared to the relevant monotherapies with either [(177)Lu]-Lu-LF1 or everolimus. [(177)Lu]-Lu-LF1 shows promise as a therapeutic radioligand for GRPR-positive prostate cancer, offering high tumor uptake and rapid clearance from nontarget tissues. Mice bearing PC3 xenograft tumors were well tolerated and demonstrated enhanced therapeutic efficacy when combined with everolimus.