Fluoroethyl Triazole Substituted PSMA Inhibitor Exhibiting Rapid Normal Organ Clearance

Ying Chen, Ala Lisok, Samit Chatterjee, Bryan Wharram, Mrudula Pullambhatla, Yuchuan Wang, George Sgouros, Ronnie C. Mease, Martin G. Pomper

Research output: Contribution to journalArticlepeer-review


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-[18F]fluoroethyl)-1H-1,2,3-triazol-yl]propanamido}pentyl)ureido]pentanedioic acid ([18F]YC-88), containing an [18F]fluoroethyl triazole moiety. [18F]YC-88 was synthesized from 2-[18F]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 [18F]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, [18F]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 [18F]YC-88 was observed. Compared to [18F]DCFPyL, which is currently in clinical trials, the uptake of [18F]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 [18F]YC-88 was significantly less than that of [18F]DCFPyL. [18F]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, [18F]YC-88 is a viable new PET radiotracer for imaging PSMA-expressing lesions.

Original languageEnglish (US)
Pages (from-to)1655-1662
Number of pages8
JournalBioconjugate Chemistry
Issue number7
StatePublished - Jul 20 2016

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry


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