Synthesis and Evaluation of11 C-Labeled Triazolones as Probes for Imaging Fatty Acid Synthase Expression by Positron Emission Tomography

James M. Kelly, Thomas M. Jeitner, Nicole N. Waterhouse, Wenchao Qu, Ethan J. Linstad, Banafshe Samani, Clarence Williams, Anastasia Nikolopoulou, Alejandro Amor-Coarasa, Stephen G. Dimagno, John W. Babich

Research output: Contribution to journalArticlepeer-review

Abstract

Cancer cells require lipids to fulfill energetic, proliferative, and signaling requirements. Even though these cells can take up exogenous fatty acids, the majority exhibit a dependency on de novo fatty acid synthesis. Fatty acid synthase (FASN) is the rate-limiting enzyme in this process. Expression and activity of FASN is elevated in multiple cancers, where it correlates with disease progression and poor prognosis. These observations have sparked interest in developing methods of detecting FASN expression in vivo. One promising approach is the imaging of radiolabeled molecular probes targeting FASN by positron emission tomography (PET). However, although [11 C]acetate uptake by prostate cancer cells correlates with FASN expression, no FASN-specific PET probes currently exist. Our aim was to synthesize and evaluate a series of small molecule triazolones based on GSK2194069, an FASN inhibitor with IC50 = 7.7 ± 4.1 nM, for PET imaging of FASN expression. These triazolones were labeled with carbon-11 in good yield and excellent radiochemical purity, and binding to FASN-positive LNCaP cells was significantly higher than FASN-negative PC3 cells. Despite these promising characteristics, however, these molecules exhibited poor in vivo pharmacokinetics and were predominantly retained in lymph nodes and the hepatobiliary system. Future studies will seek to identify structural modifications that improve tumor targeting while maintaining the excretion profile of these first-generation11 C-methyltriazolones.

Original languageEnglish (US)
Article number1552
JournalMolecules
Volume27
Issue number5
DOIs
StatePublished - Mar 1 2022
Externally publishedYes

Keywords

  • Cancer metabolism
  • Carbon-11
  • Fatty acid synthase
  • Positron emission tomography

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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