title: Synthesis, radiolabeling and initial in vivo evaluation of [(11)C]KSM-01 for imaging PPAR-α receptors.
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 (IC(50)=0.28±0.09nM) having a higher affinity to activate PPAR-α than the PPAR-α agonist GW7647 (IC(50)=0.46±0.19nM). In this study, we report the synthesis and initial in vivo evaluation of [(11)C]KSM-01. The radiosynthesis was carried out by first alkylating the corresponding p-phenol precursor with [(11)C]MeI in DMF using NaOH, followed by deprotection of the t-butyl ester group by TFA, yielding [(11)C]KSM-01. SUV analysis of dynamic micro PET/CT imaging data showed that [(11)C]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.
authors.affiliation: Division of Radiological Sciences, Washington University School of Medicine, 510 S Kingshighway Blvd, St. Louis, MO 63110, USA.
authors.forename: Kiran Kumar
authors.initials: KK
authors.lastname: Solingapuram Sai
authors.forename: Kun-Eek
authors.initials: KE
authors.lastname: Kil
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
authors.forename: Wenhua
authors.initials: W
authors.lastname: Chu
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
authors.forename: Justin M
authors.initials: JM
authors.lastname: Rothfuss
authors.forename: Kooresh I
authors.initials: KI
authors.lastname: Shoghi
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welch
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gropler
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D000818:Animals; D002087:Butyrates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007553:Isotope Labeling; D051379:Mice; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000819:agonists*; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: C577917:((11)C)KSM-01; D002087:Butyrates; D047493:PPAR alpha; D010671:Phenylurea Compounds; D019275:Radiopharmaceuticals