Preclinical Evaluation of a High-Affinity Sarcophagine-Containing PSMA Ligand for ⁶⁴Cu/⁶⁷Cu-Based Theranostics in Prostate Cancer

Abstract

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 64/67 Cu radionuclide pair for prostate cancer theranostics. RPS-085 was synthesized by conjugation of a PSMA-targeting moiety, an N ε -(2-(4iodophenyl)acetyl)lysine albumin binding group, and a bifunctionalized MeCOSar chelator. The IC 50 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 NH 4 OAc buffer at 25 °C. The stability of the radiolabeled compounds was assessed in vitro and in vivo. The biodistribution of [ 64/67 Cu]Cu-RPS-085 was determined following intravenous administration to male BALB/c mice bearing LNCaP tumor xenografts. The radiochemical yields of [ 64/67 Cu]Cu-RPS-085 were nearly quantitative after 20 min. The metal-free complex is a potent inhibitor of PSMA (IC 50 = 29 ± 2 nM), and the radiolabeled compound has moderate affinity for human serum albumin (K d = 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. [ 64 Cu]Cu-RPS-085 combines rapid tissue distribution and clearance with prolonged retention in LNCaP tumor xenografts. The pharmacokinetics should enable radioligand therapy using [ 67 Cu]Cu-RPS-085. By virtue of its rapid kidney clearance, the therapeutic index of [ 67 Cu]Cu-RPS-085 likely compares favorably to its parent structure, [ 177 Lu]Lu-RPS-063, a highly avid PSMA-targeting compound. On this basis, [ 64/67 Cu]Cu-RPS-085 show great promise as PSMA-targeting theranostic ligands for prostate cancer imaging and therapy.

Performance of 18F-DCFPyL PET/CT Imaging in Early Detection of Biochemically Recurrent Prostate Cancer: A Systematic Review and Meta-Analysis

“…Therefore, PSMA radiopharmaceuticals have been increasingly used to detect small tumor lesions, lymph node, bone, or visceral metastases because of its high sensitivity even at low PSA levels. Several PSMA radioligands such as Gallium-68 (68Ga), Fluorine-18 (18F), Lutetium-177 (177Lu), or Copper-64 (64Cu) are currently available to obtain effective radiotherapeutics for theranostic applications (16)(17)(18)(19)(20). 68Ga-PSMA PET/CT Abbreviations: PSMA, prostate-specific membrane antigen; PET/CT, positron emission tomography/computed tomography; BRPCa, biochemically recurrent prostate cancer; CI, confidence interval; DR, detection rate; PSA, prostatespecific antigen; PCa, prostate cancer; BCR, biochemical recurrence; RP, radical prostatectomy; EBRT, external beam radiation therapy; RT, radiation therapy; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses; QUADAS-2, quality assessment of diagnostic accuracy studies;…”

Implications of physics, chemistry and biology for dosimetry calculations using theranostic pairs

“…Yumi Sugo et al 54 found a similar biodistribution of [ 64 Cu]CuCl 2 in tumor-bearing mice using low SA [ 67 Cu]CuCl 2 to that calculated by Qin et al 55 using high-SA [ 64 Cu]CuCl 2 . Similarly, the biodistributions of [ 64/67 Cu]Cu-RPS-085 (a PSMA binding ligand) were similar at 4 and 24 hours post-injection when different masses were injected (31 pmol versus 17 pmol respectively) 52 although we note that the difference in injected mass is small.…”

“…67 Cu emits beta particles for therapy and gammas suitable for SPECT imaging, while 64 Cu can be imaged with PET. 67 Cu has shown similar therapeutic efficacy to 177 Lu in mouse studies for prostate cancer 52 and may be more effective than 131 I for NHL radioimmunotherapy 188 .…”

Radiolabeled PSMA Inhibitors

“…Kelly et al similarly used a sarcophagine chelator (MeCOSar) conjugated to N ε -(2-(4-iodophenyl)acetyl)lysine as albumin binding group and a PSMA binding motif (RPS-085) [ 235 ]. Uptake of [ 64 Cu]Cu-RPS-085 in LNCaP tumor bearing mice was constant for the tumor (4 h p.i.…”