Fluorine-18 labeling and biodistribution studies on peroxisome proliferator-activated receptor-gamma ligands: potential positron emission tomography imaging agents.
BACKGROUND
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is an important regulator of lipid metabolism; it controls the differentiation of preadipocytes and is also found at high levels in small metastatic tumors. In this report, we describe the radiochemical synthesis and evaluation of two (18)F-labeled analogs of the potent and selective PPARgamma agonist farglitazar.


METHODS
The isomeric aromatic fluorine-substituted target compounds [(2S)-(2-benzoylphenylamino)-3-(4-(2-[2-(4-[(18)F]fluorophenyl)-5-methyloxazol-4-yl]ethoxy)-phenyl)propionic acid ([(18)F]-1) and (2S)-[2-(4-fluorobenzoyl)phenylamino]-3-(4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-phenyl)propionic acid ([(18)F]-2)] were prepared in fluorine-18-labeled form, respectively, by radiofluorination of an iodonium salt precursor or by Ullmann-type condensation with 2-iodo-4'-[(18)F]fluorobenzophenone after nucleophilic aromatic substitution with [(18)F]fluoride ion. Each compound was obtained in high specific activity and good radiochemical yield.


CONCLUSIONS
(18)F-1 and (18)F-2 have high and selective PPARgamma binding affinities comparable to that of the parent molecule farglitazar, and they were found to have good metabolic stability. Tissue biodistribution studies of (18)F-1 and (18)F-2 were conducted, but PPARgamma-mediated uptake of both agents was minimal.


CONCLUSIONS
This study completes our first look at an important class of PPARgamma ligands as potential positron emission tomography (PET) imaging agents for breast cancer and vascular disease. Although (18)F-1 and (18)F-2 have high affinities for PPARgamma and good metabolic stability, their poor target-tissue distribution properties, which likely reflect their high lipophilicity combined with the low titer of PPARgamma in target tissues, indicate that they have limited potential as PPARgamma PET imaging agents.
Lee
Byung Chul
BC
Department of Chemistry, University of Illinois, Urbana, IL 61801, USA.
Dence
Carmen S
CS
Zhou
Haibing
H
Parent
Ephraim E
EE
Welch
Michael J
MJ
Katzenellenbogen
John A
JA
D000818:Animals; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000378:metabolism; D007553:Isotope Labeling / Q000379:methods*; D008024:Ligands; D047495:PPAR gamma / Q000378:metabolism*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D005462:Fluorine Radioisotopes; D008024:Ligands; D047495:PPAR gamma; D019275:Radiopharmaceuticals