Preclinical Evaluation of sigma up 86 Xi -Labeled Inhibitors of Prostate-Specific Membrane Antigen for Dosimetry Estimates

• Published in: The Journal of nuclear medicine (1978) Vol. 56; no. 4; p. 628
• Main Authors: Banerjee, Sangeeta Ray, Foss, Catherine A, Pullambhatla, Mrudula, Wang, Yuchuan, Srinivasan, Senthamizhchelvan, Hobbs, Robert F, Baidoo, Kwamena E, Brechbiel, Martin W, Nimmagadda, Sridhar, Mease, Ronnie C, Sgouros, George, Pomper, Martin G
• Format: Journal Article
• Language: English
• Published: 01.04.2015
• Subjects: Papio
• ISSN: 0161-5505

86Y (half-life = 14.74 h, 33% +) 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 86Y 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 90Y-labeled radiotherapeutics. Multistep syntheses were used in preparing 86Y-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 86Y-4-6 and by biodistribution studies of 86Y-4 and 86Y-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 86Y-6. Compounds 86Y-4-6 were obtained in high radiochemical yield and purity, with specific radioactivities of more than 83.92 GBq/mol. PET imaging and biodistribution studies using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu tumor-bearing mice revealed that 86Y-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 86Y-6 demonstrated the highest tumor uptake and retention, with 32.17 plus or minus 7.99 and 15.79 plus or minus 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 86Y-6. Compound 86Y-6 is a promising candidate for quantitative PET imaging of PSMA-expressing tumors. Dosimetry calculations indicate promise for future 90Y or other radiometals that could use a similar chelator/scaffold combination for radiopharmaceutical therapy based on the structure of6.