The application of small molecules targeting prostate-specific membrane
antigen (PSMA) has emerged as a highly promising clinical strategy for visualization and treatment of
prostate cancer.
Ligands that integrate the ability to both quantify the distribution of radioactivity and treat disease through the use of a matched pair of
radionuclides have particular value in clinical and regulatory settings. In this study, we describe the development and preclinical evaluation of RPS-085, a
ligand that binds PSMA and
serum albumin and exploits the 64/67Cu
radionuclide pair for
prostate cancer theranostics. RPS-085 was synthesized by conjugation of a PSMA-targeting moiety, an Nε-(2-(4-iodophenyl)acetyl)lysine
albumin binding group, and a bifunctionalized MeCOSar
chelator. The IC50 of the
metal-free RPS-085 was determined in a competitive binding assay. The affinity for
human serum albumin of the radiolabeled compound was determined by high-performance affinity chromatography. Radiolabeling was performed in NH4OAc
buffer at 25 °C. The stability of the radiolabeled compounds was assessed in vitro and in vivo. The biodistribution of [64/67Cu]Cu-RPS-085 was determined following
intravenous administration to male BALB/c mice bearing LNCaP
tumor xenografts. The radiochemical yields of [64/67Cu]Cu-RPS-085 were nearly quantitative after 20 min. The
metal-free complex is a potent inhibitor of PSMA (IC50 = 29 ± 2 nM), and the radiolabeled compound has moderate affinity for
human serum albumin (Kd = 9.9 ± 1.7 μM). Accumulation of the tracer in mice was primarily evident in
tumor and kidneys. Activity in all other tissues, including blood, was negligible, and the radiolabeled compounds demonstrated high stability in vitro and in vivo.
Tumor activity reached a maximum at 4 h post injection (p.i.) and cleared gradually over a period of 96 h. By contrast, activity in the kidney cleared rapidly from 4 to 24 h p.i. As a consequence, by 24 h p.i., the
tumor-to-kidney ratio exceeds 2, and the predicted dose to
tumors is significantly greater than the dose to kidneys. [64Cu]Cu-RPS-085 combines rapid tissue distribution and clearance with prolonged retention in LNCaP
tumor xenografts. The pharmacokinetics should enable radioligand
therapy using [67Cu]Cu-RPS-085. By virtue of its rapid kidney clearance, the therapeutic index of [67Cu]Cu-RPS-085 likely compares favorably to its parent structure, [177Lu]Lu-RPS-063, a highly avid PSMA-targeting compound. On this basis, [64/67Cu]Cu-RPS-085 show great promise as PSMA-targeting
theranostic ligands for
prostate cancer imaging and
therapy.