10.1021/jm300648b
The research focuses on the synthesis and evaluation of novel α-fluorinated derivatives based on the ABP688 structural framework, aiming to develop an optimal fluorine-18-labeled positron emission tomography (PET) radiotracer for imaging metabotropic glutamate receptor subtype 5 (mGluR5). The purpose of this research is to create a radiotracer with a longer physical half-life than the existing carbon-11 labeled tracer, [11C]-ABP688, which is limited by the short half-life of carbon-11. The researchers synthesized a series of five α-fluorinated derivatives using a two-step enolization/NFSI α-fluorination method. The most promising candidate, (Z)-16, exhibited a binding affinity (Ki) of 5.7 nM and a clogP value of 2.3. The synthesis involved various chemicals, including ethoxy enone, ethynylmagnesium bromide, SelectFluor, chlorotrimethylsilane, N-fluorobenzenesulfonimide (NFSI), and O-ethylhydroxylamine hydrochloride, among others. The research concluded that (Z)-16 is a potential mGluR5 PET radiotracer, but due to stereochemical preferences, the E-isomer of α-hydroxy derivative (E)-20 was selected for further synthesis, leading to the preparation of (E)-[18F]-16 as a model compound. This compound showed stability in vitro in plasma and PBS and specificity to mGluR5, encouraging the researchers to explore alternative routes to access the Z-isomer selectively.
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