Development of Novel Fluorine-18 Labeled PET Tracers for Imaging of the Metabotropic Glutamate Receptor Subtype 5 (mGluR5)

Intensive investigations during the last years have shown that metabotropic glutamate receptors are involved in numerous neurodegenerative diseases such as M. Parkinson, M. Alzheimer and M. Huntington as well as other central nervous system disorders including neurogenic pain, epilepsy, depression and drug addiction. The neurobiological basis of these impairments is, however, still not well understood. Non-invasive imaging techniques such as positron emission tomography (PET) offer the possibility to visualize and analyze CNS receptors such as mGluR5 under various physiological and pathophysiological conditions. Although the PET technology is well advanced, the imaging of mGluR5 in humans is limited by the lack of high-affinity and selective PET radioligands. Very recently, our group reported on the development of the carbon-11 labeled PET ligand, [ 11 C]-ABP688 with which the first imaging of mGluR5 in humans succeeded. Carbon-11 has a relatively short physical half-life of 20 min. Fluorine-18, however, has the best imaging characteristics of all PET radionuclides due to its low positron energy and in addition, its half-life of 110 min allows for complex synthesis and longer in vivo investigations. Most importantly, the long physical half-life of fluorine-18 enables " satellite " distribution to clinical PET centers not equipped with radiochemistry facilities. Prompted by the need to develop a fluorine-18 labeled PET radiotracer for imaging mGluR5 in vivo, a series of fluorinated compounds based on the core structure of ABP688 were synthesized. The candidates were designed such that the fluorine atom is conveniently placed to allow a one-step radiosynthesis with fluorine-18. ABP688 consists of a linker that connects a pyridine moiety with a cyclohexenoneoxime moiety. Accordingly, two general concepts for the introduction of fluorine were considered. In the first approach, possibilities for the introduction of fluorine at the aromatic moiety of the molecules represented in ABP688 by a pyridine ring were considered. Therefore ABP688 analogues in which the position of the nitrogen atom in the pyridine ring was shifted and several non-fluorinated and fluorinated derivatives in which the pyridine ring was replaced by a thiazole moiety were synthesized. The second approach entailed the replacement of the methyl group at the oxime functionality in ABP688 by ethoxy fluorine containing aliphatic side chains, fluoropyridines and fluorobenzonitriles. 10 In total, 17 novel candidates were synthesized by convergent syntheses involving Sonogashira coupling. The compounds were obtained in overall good to optimal yields and were fully characterized by mass spectroscopy and NMR spectroscopy. Each molecule was evaluated for …