Synthesis and evaluation of 18F-labeled PPARγ antagonists

Area of Science:

• Radiochemistry
• Molecular Imaging
• Pharmacology

Background:

• Peroxisome proliferator-activated receptor gamma (PPARγ) regulates fat metabolism and is implicated in diseases like cancer and inflammation.
• PPARγ imaging agents are valuable tools for studying these pathological conditions.

Purpose of the Study:

• To synthesize and evaluate novel PPARγ antagonists for potential use as PET imaging agents.
• To assess the in vivo imaging capabilities of these compounds in a relevant disease model.

Main Methods:

• Synthesis of four GW9662 analogs with varying fluorine substituents.
• Evaluation of receptor binding affinity using scintillation proximity and whole-cell assays.
• Micro-positron emission tomography (PET) imaging in a transgenic mouse model with heart-specific PPARγ overexpression.

Main Results:

• Four analogs exhibited comparable or better binding affinity than GW9662 in SPA assays.
• Only chloro-based analogs (compounds 3 and 4) showed activity in whole-cell assays.
• The irreversible antagonist [(18F]3 demonstrated high uptake and specific PPARγ binding in vivo, unlike its reversible counterpart [(18F]5.

Conclusions:

• The irreversible antagonist [(18F]3 is a promising candidate for in vivo PPARγ imaging via PET.
• This compound represents a novel strategy for visualizing PPARγ in pathological conditions.