Preclinical Evaluation of 86Y-Labeled Inhibitors of Prostate Specific Membrane Antigen for Dosimetry Estimates

Y-86 (half-life = 14.74 h, 33% beta(+)) is within an emerging class of positron-emitting isotopes with relatively long physical half-lives that enables extended imaging of biologic processes. We report the synthesis and evaluation of 3 low-molecular-weight compounds labeled with Y-86 for imaging the prostate-specific membrane antigen (PSMA) using PET. Impetus for the study derives from the need to perform dosimetry estimates for the corresponding Y-90-labeled radiotherapeutics. Methods: Multistep syntheses were used in preparing Y-86-4-6. PSMA inhibition constants were evaluated by competitive binding assay. In vivo characterization using tumor-bearing male mice was performed by PET/CT for Y-86-4-6 and by biodistribution studies of Y-86-4 and Y-86-6 out to 24 h after injection. Quantitative whole-body PET scans were recorded to measure the kinetics for 14 organs in a male baboon using Y-86-6. Results: Compounds Y-86-4-6 were obtained in high radiochemical yield and purity, with specific radioactivities Of more than 83.92 GBq/mu mol. PET imaging and biodistribution studies using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu tumor-bearing mice revealed that Y-86-4-6 had high site-specific uptake in PSMA-positive PC-3 PIP tumor starting at 20 min after injection and remained high at 24 h. Compound Y-86-6 demonstrated the highest tumor uptake and retention, with 32.17 +/- 7.99 and 15.79 +/- 6.44 percentage injected dose per gram (%ID/g) at 5 and 24 h, respectively. Low activity concentrations were associated with blood and normal organs, except for the kidneys, a PSMA-expressing tissue. PET imaging in baboons reveals that all organs have a 2-phase (rapid and slow) clearance, with the highest uptake (8 %ID/g) in the kidneys at 25 min. The individual absolute uptake kinetics were used to calculate radiation doses using the OLINDA/EXM software. The highest mean absorbed dose was received by the renal cortex, with 1.9 mGy per MBq of Y-86-6. Conclusion: Compound Y-86-6 is a promising candidate for quantitative PET imaging of PSMA-expressing tumors. Dosimetry calculations indicate promise for future Y-90 or other radiometals that could use a similar chelator/scaffold combination for radiopharmaceutical therapy based on the structure of 6.