Synthesis, radiolabeling and initial in vivo evaluation of [ 11C]KSM-01 for imaging PPAR-α receptors

Kiran Kumar Solingapuram Sai, Kun Eek Kil, Zhude Tu, Wenhua Chu, Brian N. Finck, Justin M. Rothfuss, Kooresh I. Shoghi, Michael J. Welch, Robert J. Gropler, Robert H. Mach

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Peroxisome proliferator-activated receptor alpha (PPAR-α) is a ligand-activated nuclear receptor transcription factor that regulates the fatty acid β-oxidation. An in vitro assay identified the p-methoxy phenyl ureido thiobutyric acid derivative KSM-01 (IC50 = 0.28 ± 0.09 nM) having a higher affinity to activate PPAR-α than the PPAR-α agonist GW7647 (IC50 = 0.46 ± 0.19 nM). In this study, we report the synthesis and initial in vivo evaluation of [11C]KSM-01. The radiosynthesis was carried out by first alkylating the corresponding p-phenol precursor with [11C]MeI in DMF using NaOH, followed by deprotection of the t-butyl ester group by TFA, yielding [11C]KSM-01. SUV analysis of dynamic micro PET/CT imaging data showed that [11C]KSM-01 accumulation was ∼2.0-fold greater in cardiac-specific PPAR-α overexpressing transgenic mice compared to wild-type littermates. The post-PET biodistribution studies were consistent with these results and demonstrated 2.5-fold greater radiotracer uptake in the heart of transgenic mice compared to the wild-type littermates. These results demonstrate the potential utility of PPAR-α agonists as PET radiopharmaceuticals.

Original languageEnglish
Pages (from-to)6233-6236
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number19
DOIs
StatePublished - Oct 1 2012

Keywords

  • Cardiomyopathy
  • PET imaging
  • Peroxisome proliferator-activated receptor alpha (PPAR-α)
  • Ureido thioisobutyric acid (TiBA)
  • β-Oxidation

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