[(18)F]Fluoroethyl Triazole Substituted PSMA Inhibitor Exhibiting Rapid Normal Organ Clearance.
Prostate-specific membrane antigen (PSMA) is overexpressed in the epithelium of prostate cancer and nonprostate solid tumor neovasculature. PSMA is increasingly utilized as a target for cancer imaging and therapy. Here, we report the synthesis and in vivo biodistribution of a low-molecular-weight PSMA-based imaging agent, 2-[3-(1-carboxy-5-{3-[1-(2-[(18)F]fluoroethyl)-1H-1,2,3-triazol-yl]propanamido}pentyl)ureido]pentanedioic acid ([(18)F]YC-88), containing an [(18)F]fluoroethyl triazole moiety. [(18)F]YC-88 was synthesized from 2-[(18)F]fluoroethyl azide and the corresponding alkyne precursor in two steps using either a one- or two-pot procedure. Biodistribution and positron emission tomography (PET) imaging were performed in immunocompromised mice using isogenic PSMA(+) PC3 PIP and PSMA(-) PC3 flu xenografts. YC-88 exhibited high affinity for PSMA as evidenced by a Ki value of 12.9 nM. The non-decay corrected radiochemical yields of [(18)F]YC-88 averaged 14 ± 1% (n = 5). Specific radioactivities ranged from 320 to 2,460 Ci/mmol (12-91 GBq/μmol) with an average of 940 Ci/mmol (35 GBq/μmol, n = 5). In an immunocompromised mouse model, [(18)F]YC-88 clearly delineated PSMA(+) PC3 PIP prostate tumor xenografts on imaging with PET. At 1 h postinjection, 47.58 ± 5.19% injected dose per gram of tissue (% ID/g) was evident within the PSMA(+) PC3 PIP tumor, with a ratio of 170:1 of uptake within PSMA(+) PC3 PIP to PSMA(-) PC3 flu tumor placed in the opposite flank. The tumor-to-kidney ratio at 2 h postinjection was 4:1. At or after 30 min postinjection, minimal nontarget tissue uptake of [(18)F]YC-88 was observed. Compared to [(18)F]DCFPyL, which is currently in clinical trials, the uptake of [(18)F]YC-88 within the kidney, liver, and spleen was significantly lower at all time-points studied. At 30 min and 1 h postinjection, salivary gland uptake of [(18)F]YC-88 was significantly less than that of [(18)F]DCFPyL. [(18)F]YC-88 is a new PSMA-targeted PET agent synthesized utilizing click chemistry that demonstrates high PSMA(+) tumor uptake in a xenograft model. Because of its low uptake in the kidney, rapid clearance from nontarget organs, and relatively simple one-pot, two-step radiosynthesis, [(18)F]YC-88 is a viable new PET radiotracer for imaging PSMA-expressing lesions.
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions , Baltimore, Maryland 21287, United States.
Ying
Y
Chen
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions , Baltimore, Maryland 21287, United States.
Ala
A
Lisok
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions , Baltimore, Maryland 21287, United States.
Samit
S
Chatterjee
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions , Baltimore, Maryland 21287, United States.
Bryan
B
Wharram
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions , Baltimore, Maryland 21287, United States.
Mrudula
M
Pullambhatla
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions , Baltimore, Maryland 21287, United States.
Yuchuan
Y
Wang
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions , Baltimore, Maryland 21287, United States.
George
G
Sgouros
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions , Baltimore, Maryland 21287, United States.
Ronnie C
RC
Mease
The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions , Baltimore, Maryland 21287, United States.
Martin G
MG
Pomper
D000818:Animals; D000954:Antigens, Surface; D045744:Cell Line, Tumor; D057930:Click Chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014230:Triazoles / Q000737:chemistry*
D000954:Antigens, Surface; D004791:Enzyme Inhibitors; D014230:Triazoles; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II