TY - JOUR
T1 - Preclinical evaluation of 86Y-labeled inhibitors of prostate-specific membrane antigen for dosimetry estimates
AU - Banerjee, Sangeeta Ray
AU - Foss, Catherine A.
AU - Pullambhatla, Mrudula
AU - Wang, Yuchuan
AU - Srinivasan, Senthamizhchelvan
AU - Hobbs, Robert F.
AU - Baidoo, Kwamena E.
AU - Brechbiel, Martin W.
AU - Nimmagadda, Sridhar
AU - Mease, Ronnie C.
AU - Sgouros, George
AU - Pomper, Martin G.
N1 - Publisher Copyright:
COPYRIGHT © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - 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.
AB - 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.
KW - Molecular imaging
KW - PET
KW - PSMA
KW - Radiopharmaceutical therapy
KW - Y-DOTA
UR - http://www.scopus.com/inward/record.url?scp=84928237478&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84928237478&partnerID=8YFLogxK
U2 - 10.2967/jnumed.114.149062
DO - 10.2967/jnumed.114.149062
M3 - Article
C2 - 25722448
AN - SCOPUS:84928237478
SN - 0161-5505
VL - 56
SP - 628
EP - 634
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 4
ER -