Synthesis and biodistribution of (11)C-GW7845, a positron-emitting agonist for peroxisome proliferator-activated receptor-{gamma}.
The goal of this study was to synthesize and evaluate in vivo the peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist (11)C-GW7845 ((S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}ethylamino)benzoic acid methyl ester) ((11)C-compound 1). PPARgamma is a member of a family of nuclear receptors that plays a central role in the control of lipid and glucose metabolism. Compound 1 is an analog of tyrosine (inhibitor constant, 3.7 nmol/L), which is an inhibitor of experimental mammary carcinogenesis.


METHODS
Protection of the carboxylic acid moiety of compound 1 was effected by treatment with N,N-dimethylformamide di-tert-butyl acetal to provide compound 2. Hydrolysis of the carbomethoxy group of compound 2 provided the benzoic acid (compound 3) that served as an immediate precursor to radiolabeling. Compound 3 underwent treatment with (11)C-methyl iodide followed by high-performance liquid chromatography to produce a radioactive peak sample that coeluted with a standard sample of compound 1. Analysis of biodistribution was undertaken by injecting male CD-1 mice via the tail vein with 6.03 MBq (163 microCi, 2.55 microg/kg) of (11)C-compound 1. To determine the tumor uptake of the radiotracer, 6 female SCID mice bearing MCF-7 xenografts were injected via the tail vein with 10.5 MBq (283 microCi, 0.235 microg/kg) of (11)C-compound 1.


RESULTS
(11)C-Compound 1 was synthesized at an 8% radiochemical yield in 29 min with an average specific radioactivity of 1,222 GBq/micromol (33,024 mCi/micromol; n = 6) at the end of synthesis. Spleen (target)-to-muscle uptake and tumor-to-muscle uptake ratios were 3.1 and 1.5, respectively, but this uptake could not be blocked with unlabeled compound 1 at 2 mg/kg.


CONCLUSIONS
Further structural modification, perhaps to generate a less lipophilic tyrosine analog, will be necessary to enable receptor-mediated PPARgamma imaging by this class of agents.
Mathews
William B
WB
Department of Radiology, Johns Hopkins University, Baltimore, Maryland 21287, USA.
Foss
Catherine A
CA
Stoermer
Doris
D
Ravert
Hayden T
HT
Dannals
Robert F
RF
Henke
Brad R
BR
Pomper
Martin G
MG
D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D016513:Mice, SCID; D009928:Organ Specificity; D010080:Oxazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics
D002250:Carbon Radioisotopes; D010080:Oxazoles; D047495:PPAR gamma; D019275:Radiopharmaceuticals; C401311:GW 7845; D014443:Tyrosine