Preclinical evaluation of 86Y-labeled inhibitors of prostate-specific membrane antigen for dosimetry estimates.
(86)Y (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-molecular-weight compounds labeled with (86)Y 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 (90)Y-labeled radiotherapeutics.


METHODS
Multistep syntheses were used in preparing (86)Y- 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 (86)Y- 4: - 6: and by biodistribution studies of (86)Y- 4: and (86)Y- 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 (86)Y- 6 RESULTS: Compounds (86)Y- 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 (86)Y- 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 (86)Y- 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 (86)Y- 6:


CONCLUSIONS
Compound (86)Y- 6: is a promising candidate for quantitative PET imaging of PSMA-expressing tumors. Dosimetry calculations indicate promise for future (90)Y or other radiometals that could use a similar chelator/scaffold combination for radiopharmaceutical therapy based on the structure of 6.
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland; and mpomper@jhmi.edu sray9@jhmi.edu.
Sangeeta Ray
SR
Banerjee
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland; and.
Catherine A
CA
Foss
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland; and.
Mrudula
M
Pullambhatla
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland; and.
Yuchuan
Y
Wang
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland; and.
Senthamizhchelvan
S
Srinivasan
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland; and.
Robert F
RF
Hobbs
National Institutes of Health, Bethesda, Maryland.
Kwamena E
KE
Baidoo
National Institutes of Health, Bethesda, Maryland.
Martin W
MW
Brechbiel
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland; and.
Sridhar
S
Nimmagadda
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland; and.
Ronnie C
RC
Mease
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland; and.
George
G
Sgouros
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland; and mpomper@jhmi.edu sray9@jhmi.edu.
Martin G
MG
Pomper
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D045744:Cell Line, Tumor; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D010215:Papio; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011874:Radiometry / Q000379:methods*; D019275:Radiopharmaceuticals; D012984:Software; D013997:Time Factors; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed; D015021:Yttrium Radioisotopes / Q000493:pharmacokinetics
D000954:Antigens, Surface; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
86Y-DOTA; PET; PSMA; molecular imaging; radiopharmaceutical therapy