A PSMA Ligand Labeled with Cobalt-55 for PET Imaging of Prostate Cancer

Prostate-specific membrane antigen (PSMA) comprises a recognized target for molecular imaging of prostate cancer. As such, radiolabeled PSMA inhibitors are of great value for diagnosis and staging of this disease. Herein, we disclose the preclinical characterization of [⁵⁵Co]PSMA-617 for positron emission tomography (PET)/x-ray computed tomography (CT) imaging of prostate cancer lesions.

By the application of microwave heating, PSMA-617 in acetate buffer (0.4 M, pH 4.4) was labeled with the radioisotopes cobalt-55/57. The extents of internalization and dissociation constants (K _D) were determined against 2-(phosphonomethyl)-pentanedioic acid in two PSMA-positive cell lines, LNCaP, and PC3-PIP, with [⁵⁷Co]PSMA-617 as a surrogate for [⁵⁵Co]PSMA-617 (T½ 17.5 h, β _max 1.5 MeV, Iβ 76 %). The biodistribution in LNCaP xenograft mice was investigated using [⁵⁷Co]PSMA-617 and [⁵⁵Co]PSMA-617 was employed for PET/CT imaging at 1, 4, and 24 h and compared to PET/CT scans using [⁶⁸Ga]PSMA-617.

The radiolabeling with cobalt-55/57 was performed in yields greater than 99.5 and 99.8 % and radiochemical purities of 99.7 and 98.9 %, respectively. The molar-specific activities were 18.2 MBq/nmol and 3.3 MBq/nmol. The cellular K _D were determined to be 4.7 nM for LNCaP and 9.8 nM for PC3-PIP, correspondingly. Internalization of 76 and 71 % of the cell-associated radioactivity was found for LNCaP and PC3-PIP cells after incubation up to 240 min, respectively. In regard to the biodistribution in LNCaP xenograft mice, [⁵⁷Co]PSMA-617 displayed a high and relatively constant uptake in the tumor (12.9 %IA/g at 1 h to 10.5 %IA/g at 24 h) with an initial but transient high uptake in the kidneys, adrenals, and spleen. Tumor-to-background ratios improved over time as normal tissue cleared of the radioligand (tumor-to-blood: 26, 258, and 3013; tumor-to-kidney: 0.11, 0.28, and 4.3 at 1, 4, and 24 h). PET/CT imaging with [⁵⁵Co]PSMA-617 in xenograft mice confirmed the high tumor uptake and fast clearance of normal tissues over time and was found superior to imaging with [⁶⁸Ga]PSMA-617.

Radiolabeling of PSMA-617 was achieved in excellent yields and radiochemical purities. Favorable in vitro data comprising low K _D values and high extent of internalization was determined for two PSMA-positive cell lines. In xenograft mice, high tumor accumulation and excellent tumor-to-normal tissues ratios were established by biodistribution experiments and PET/CT imaging and, hence, confirm the potential of [⁵⁵Co]PSMA-617 for delayed clinical imaging of prostate cancer.