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

ABSTRACT: Peroxisome proliferator-activated receptor alpha (PPAR-?) is a ligand-activated nuclear receptor transcription factor that regulates the fatty acid ?-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-? than the PPAR-? 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-? 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-? agonists as PET radiopharmaceuticals.

SUBMITTER: Solingapuram Sai KK

PROVIDER: S-EPMC3477601 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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

Solingapuram Sai Kiran Kumar KK Kil Kun-Eek KE Tu Zhude Z Chu Wenhua W Finck Brian N BN Rothfuss Justin M JM Shoghi Kooresh I KI Welch Michael J MJ Gropler Robert J RJ Mach Robert H RH

Bioorganic & medicinal chemistry letters 20120809 19

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 fir ...[more]

PMID: 22939697

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Project description:UNLABELLED: BACKGROUND:To date, few PET tracers for in vivo labeling of red blood cells (RBCs) are available. In this study, we report the radiosynthesis and in vitro and in vivo evaluation of 11C and 18F sulfonamide derivatives targeting carbonic anhydrase II (CA II), a metallo-enzyme expressed in RBCs, as potential blood pool tracers. A proof-of-concept in vivo imaging study was performed to demonstrate the feasibility to assess cardiac function and volumes using electrocardiogram (ECG)-gated positron emission tomography (PET) acquisition in comparison with cine magnetic resonance imaging (cMRI) in rats and a pig model of myocardial infarction. METHODS:The inhibition constants (Ki) of CA II were determined in vitro for the different compounds by assaying CA-catalyzed CO2 hydration activity. Binding to human RBCs was estimated after in vitro incubation of the compounds with whole blood. Biodistribution studies were performed to evaluate tracer kinetics in NMRI mice. ECG-gated PET acquisition was performed in Wistar rats at rest and during pharmacological stress by infusing dobutamine at 10 ?g/kg/min and in a pig model of myocardial infarction. Left ventricular ejection fraction (LVEF) and volumes were compared with values from cMRI. RESULTS:The Ki of the investigated compounds for human CA II was found to be in the range of 8 to 422 nM. The fraction of radioactivity associated with RBCs was found to be ?90% at 10- and 60-min incubation of tracers with heparinized human blood at room temperature for all tracers studied. Biodistribution studies in mice indicated that 30% to 67% of the injected dose was retained in the blood pool at 60 min post injection. A rapid and sustained tracer uptake in the heart region with an average standardized uptake value of 2.5 was observed from micro-PET images. The LVEF values obtained after pharmacological stress in rats closely matched between the cMRI and micro-PET values, whereas at rest, a larger variation between LVEF values obtained by both techniques was observed. In the pig model, a good agreement was observed between PET and MRI for quantification of left ventricular volumes and ejection fraction. CONCLUSIONS:The 11C and 18F sulfonamide derivatives can be used for efficient in vivo radiolabeling of RBCs, and proof-of-concept in vivo imaging studies have shown the feasibility and potential of these novel tracers to assess cardiac function.

Dataset Information

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

Publications

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

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