Synthesis and Evaluation of 11C-Labeled Triazolones as Probes for Imaging Fatty Acid Synthase Expression by Positron Emission Tomography. Academic Article uri icon

Overview

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 [11C]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-generation 11C-methyltriazolones.

authors

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

publication date

  • February 25, 2022

Research

keywords

  • Fatty Acid Synthases

Identity

PubMed Central ID

  • PMC8911806

Scopus Document Identifier

  • 85125191094

Digital Object Identifier (DOI)

  • 10.1016/j.ejps.2020.105321

PubMed ID

  • 35268652

Additional Document Info

volume

  • 27

issue

  • 5