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 Selena Milicevic Sephton, † Linjing Mu, † W. Bernd Schweizer, ‡ Roger Schibli, † Stefanie D. Kra ̈ mer, † and Simon M. Ametamey* ,† † 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 ‡ Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH) Zurich, Wolfgang-Pauli Strasse 10, 8093 Zurich, Switzerland * S Supporting Information 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. ■ INTRODUCTION Positron emission tomography (PET) is a noninvasive imaging technique in which 3D concentration images are obtained through computational analysis of pairs of γ rays emitted indirectly from compounds containing positron emitting nuclides such as [ 11 C] or [ 18 F]. 1-3 Metabotropic glutamate receptor subtype 5 (mGluR5) is a G-protein-coupled postsynaptic receptor, and it belongs to group I of metabotropic glutamate receptors, which together with ionotropic glutamate receptors regulate glutamate, a major excitatory neurotransmitter in mammalian brain. 4-8 In 2006, the Ametamey group reported on the synthesis, radiolabeling, and pharmacological evaluation of [ 11 C]-1 ([ 11 C]-ABP688, Figure 1) and subsequently illustrated its application as a PET radiotracer for imaging of mGluR5 in vivo in human subjects. 9-11 The success of this first mGluR5 PET tracer was immediate, and [ 11 C]-1 was employed in many clinical studies 12-19 particularly because mGluR5 emerged as an important drug target due to its demonstrated involvement in long-term potentiation processes as well as several CNS disorders 20 (e.g., schizophrenia, 21 depression, 22 neuropathic pain, 23,24 drug addiction, 25 Fragile X syndrome, 26 and Alzheimer’s 19,27 and Parkinson’s disease 28,29 ). Although clin- ically applied with success, [ 11 C]-1 has one significant limitation which is the short physical half-life (20 min) of the carbon-11 nuclide that limits its application to facilities with an on-site cyclotron. This opened the possibility for further advancement of mGluR5 PET tracers with the aim of designing a fluorine-18- labeled tracer. Received: May 9, 2012 Published: July 23, 2012 Figure 1. Structures of carbon-11 and fluorine-18 mGluR5 PET radiotracers from the Ametamey group and the synthetic plan to a new series of α-fluorinated analogues of 1. A crossed double bond is used to indicate double bond isomers (E and Z). Article pubs.acs.org/jmc © 2012 American Chemical Society 7154 dx.doi.org/10.1021/jm300648b | J. Med. Chem. 2012, 55, 7154-7162