title: Synthesis and evaluation of novel α-fluorinated (E)-3-((6-methylpyridin-2-yl)ethynyl)cyclohex-2-enone-O-methyl oxime (ABP688) derivatives as metabotropic glutamate receptor subtype 5 PET radiotracers.
abstract: In the search for an optimal fluorine-18-labeled positron emission tomography (PET) radiotracer for imaging metabotropic glutamate receptor subtype 5 (mGluR5), we have prepared a series of five α-fluorinated derivatives based on the ABP688 structural manifold by application of a two-step enolization/NFSI α-fluorination method. Their binding affinities were evaluated in vitro, and the most promising candidate (Z)-16 exhibited a K(i) of 5.7 nM and a clogP value of 2.3. The synthesis of the precursor tosylate (E)-22 revealed a preference for the (E)-configurational isomer (K(i) = 31.2 nM), and successful radiosynthesis afforded (E)-[(18)F]-16 which was used as a model PET tracer to establish plasma and PBS stability. (E)-[(18)F]-16 (K(d) = 70 nM) exhibited excellent specificity for mGluR5 in autoradiographic studies on horizontal rat brain slices in vitro.
authors: Center for Radiopharmaceutical Sciences of ETH, PSI and USZ, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zurich, Wolfgang-Pauli Strasse 10, 8093 Zurich, Switzerland.
authors: Selena
authors: S
authors: Milicevic Sephton
authors: Linjing
authors: L
authors: Mu
authors: W Bernd
authors: WB
authors: Schweizer
authors: Roger
authors: R
authors: Schibli
authors: Stefanie D
authors: SD
authors: Krämer
authors: Simon M
authors: SM
authors: Ametamey
mesh_terms: D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D018360:Crystallography, X-Ray; D005462:Fluorine Radioisotopes; D066298:In Vitro Techniques; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C510950:3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime; D005462:Fluorine Radioisotopes; C578937:Grm5 protein, rat; D010091:Oximes; D011725:Pyridines; D019275:Radiopharmaceuticals; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate