Strategies for the labeling of halogen-substituted peroxisome proliferator-activated receptor gamma ligands: potential positron emission tomography and single photon emission computed tomography imaging agents.
Well-known as an important regulator of lipid metabolism and adipocyte differentiation, the peroxisome proliferator-activated receptor gamma (PPARgamma) also has potential use as a target for antitumor therapy in certain cancers. To develop agents for radionuclide imaging PPARgamma in vivo, we synthesized fluorine, bromine, and iodine-substituted analogs (1-3) of a high-affinity benzophenone-tyrosine PPARgamma ligand; all three analogs retain very high affinity for the PPARgamma receptor. In preparation for the synthesis of these PPARgamma ligands in radiolabeled form, we have synthesized two types of precursors: (a) an aryltributylstannane (9), from which the bromine and iodine-substituted analogs (2 and 3) can readily be prepared by electrophilic destannylation, and (b) three diaryliodonium tosylate derivatives (12a-c), precursors for nucleophilic aromatic fluorination using fluoride ion. Conditions were developed whereby the thiophenyliodonium tosylate (12c) underwent nucleophilic aromatic substitution with fluoride ion, efficiently and in short reaction times, to produce the desired fluorine-substituted target compound 1. These reactions laid the groundwork for producing these three PPARgamma ligands in radiolabeled form; in addition, our use of diaryliodonium ion precursors for aromatic fluorination in this series provides an example that should encourage application of this approach for radiofluorination of more complicated radiopharmaceuticals.
Lee
Byung Chul
BC
Department of Chemistry, University of Illinois, Urbana, Illinois 61801, Laboratory of Radiopharmaceuticals, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
Lee
Kyo Chul
KC
Lee
Hsiaoju
H
Mach
Robert H
RH
Katzenellenbogen
John A
JA
D001577:Benzophenones / Q000737:chemistry; D001966:Bromine / Q000737:chemistry*; D005461:Fluorine / Q000737:chemistry*; D005462:Fluorine Radioisotopes; D007455:Iodine / Q000737:chemistry*; D007457:Iodine Radioisotopes; D008024:Ligands; D047495:PPAR gamma / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon; D014443:Tyrosine / Q000737:chemistry
D001577:Benzophenones; D005462:Fluorine Radioisotopes; D007457:Iodine Radioisotopes; D008024:Ligands; D047495:PPAR gamma; D019275:Radiopharmaceuticals; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D005461:Fluorine; D014443:Tyrosine; C047723:benzophenone; D007455:Iodine; D001966:Bromine