Molecular Imaging for Radiolabeling a PSMA-Targeted Long Circulating Peptide as a Theranostic Agent in Mice Bearing a Human Prostate Tumor

177Lu-PSMA-617 is a promising radiotheranostic agent for metastatic castration-resistant prostate cancer (mCRPC) patients that is composed of prostate-specific membrane antigen (PSMA) conjugated with 177Lu. PSMA-INER-56 is a molecule with PSMA-617 targeting activity and an albumin-binding motif and extends the blood retention time. PSMA-INER-56 is radiolabeled with indium-111 (111In) as a diagnostic agent and with lutetium-177 (177Lu) as a therapeutic agent. This study determines the efficacy of molecular targeted imaging and the preliminary therapeutic effect of 111In/177Lu-PSMA-INER-56 in PSMA expressing mice that bear a prostate tumor mice. The stability of 111In-PSMA-INER-56 and 177Lu-PSMA-INER-56 is evaluated in normal saline and human serum. Head-to-head comparisons between 177Lu-PSMA-INER-56 and 177Lu-PSMA-617 use NanoSPECT/CT molecular imaging to determine the distribution, targeting and anti-tumor efficacy in LNCaP tumor-bearing mice. The radiochemical purity of 111In-PSMA-INER-56 or 177Lu-PSMA-INER-56 is 99.09 ± 0.38 and 98.87 ± 0.73%, respectively. The in vitro stability for both radio-labeled peptides is more than 95% up to 96 h. The greatest uptake of 111In-PSMA-INER-56 or 177Lu-PSMA-INER-56 in the tumor occurs at 24 h. The uptake is 43.78 ± 6.55 and 22.08 ± 6.63%ID/g, respectively. The 177Lu-PSMA-INER-56 more effectively inhibits tumor growth (96.0%) than 177Lu-PSMA-617 (54.7%) 44 days post injection (p.i). PSMA-INER-56 that is labeled with 111In or 177Lu is demonstrated to be a potential radiotheranostic pair for PSMA-positive tumors. 177Lu-PSMA-INER-56 also exhibits better targeting than 177Lu-PSMA-617.