Radiochemical and Biological Evaluation of 3p-C-NETA-ePSMA-16, a Promising PSMA-Targeting Agent for Radiotheranostics

Bifunctional chelators (BFCs) are a key element in the design of radiopharmaceuticals. By selecting a BFC that efficiently complexes diagnostic and therapeutic radionuclides, a theranostic pair possessing almost similar biodistribution and pharmacokinetic properties can be developed. We have previously reported 3p-C-NETA as a promising theranostic BFC, and the encouraging preclinical outcomes obtained with [F-18]AlF-3p-C-NETA-TATE led us to conjugate this chelator to a PSMA-targeting vector for imaging and treatment of prostate cancer. In this study, we synthesized 3p-C-NETA-ePSMA-16 and radiolabeled it with different diagnostic (In-111, F-18) and therapeutic (Lu-177, Bi-213) radionuclides. 3p-C-NETA-ePSMA-16 showed high affinity to PSMA (IC50 = 4.61 & PLUSMN; 1.33 nM), and [In-111]In-3p-C-NETA-ePSMA-16 showed specific cell uptake (1.41 & PLUSMN; 0.20% ID/10(6) cells) in PSMA expressing LS174T cells. Specific tumor uptake of [In-111]In-3p-C-NETA-ePSMA-16 was observed up to 4 h p.i. (1.62 & PLUSMN; 0.55% ID/g at 1 h p.i.; 0.89 & PLUSMN; 0.58% ID/g at 4 h p.i.) in LS174T tumor-bearing mice. Only a faint signal could be seen at 1 h p.i. in the SPECT/CT scans, whereas dynamic PET/CT scans performed after administration of [F-18]AlF-3p-C-NETA-ePSMA-16 in PC3-Pip tumor xenografted mice resulted in a better tumor visualization and imaging contrast. Therapy studies with short-lived radionuclides such as Bi-213 could further elucidate the therapeutic potential of 3p-C-NETA-ePSMA-16 as a radiotheranostic.

Automated summary

In this study, 3p-C-NETA-ePSMA-16 was synthesized and showed high affinity to PSMA, as well as specific uptake in PSMA expressing cells and tumors. It also exhibited improved tumor visualization and imaging contrast compared to other radiopharmaceuticals. Furthermore, 3p-C-NETA-ePSMA-16 has potential for radiotherapy.