Preclinical evaluation of 86Y-labeled inhibitors of prostate-specific membrane antigen for dosimetry estimates

Sangeeta Ray Banerjee, Catherine A. Foss, Mrudula Pullambhatla, Yuchuan Wang, Senthamizhchelvan Srinivasan, Robert F. Hobbs, Kwamena E. Baidoo, Martin W. Brechbiel, Sridhar Nimmagadda, Ronnie C. Mease, George Sgouros, Martin G. Pomper

Research output: Contribution to journalArticlepeer-review

Abstract

86Y (half-life = 14.74 h, 33% β+) 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-molecularweight compounds labeled with 86Y for imaging the prostatespecific membrane antigen (PSMA) using PET. Impetus for the study derives from the need to perform dosimetry estimates for the corresponding 90Y-labeled radiotherapeutics. Methods: 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. Results: Compounds 86Y-4-6 were obtained in high radiochemical yield and purity, with specific radioactivities of more than 83.92 GBq/μmol. 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 ± 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 86Y-6. Conclusion: 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 of 6.

Original languageEnglish (US)
Pages (from-to)628-634
Number of pages7
JournalJournal of Nuclear Medicine
Volume56
Issue number4
DOIs
StatePublished - Apr 1 2015

Keywords

  • Molecular imaging
  • PET
  • PSMA
  • Radiopharmaceutical therapy
  • Y-DOTA

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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