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Molecular Imaging Branch (MIB)

1.4 Radiotracers for mGluR5 receptors

1 Ligand Development

1.4 Radiotracers for mGluR5 receptors

Glutamate is the major brain excitatory neurotransmitter and acts on a myriad of receptors that may be implicated in neuropsychiatric disorders. Subtype-5 metabotropic glutamate receptors (mGluR5) have received a high level of attention because of their possible involvement in, for example, PD, anxiety disorders and schizophrenia, and their possibility to function as a target for drug therapies.61 High affinity allosteric antagonists have been developed for mGluR5 opening up the possibility to develop PET radiotracers for their imaging in brain.62 We collaborated with Prof. Kozikowski and also with Dr. G. Tamagnan (Yale U.) to identify and synthesize high affinity ligands amenable to labeling with positron-emitters. From these interactions we prepared and advanced several candidate radiotracers for evaluation with PET in rat and rhesus monkey. These radiotracers were derived from three ethynyl-type structural leads, namely MPEP (2-methyl-6-(2-phenylethynyl)pyridine),63 PEPy (5-(2- (pyridin-2-yl)-ethyn-yl)pyridine)64 and MTEP (3-(2-(2-methylthia-zol- 4-yl)-ethynyl)-pyridine)65. Our choice of candidates was based on high affinity (criterion: Kd or IC50, > 5 nM), as reported in various assays or determined through assay services (Novascreen or PDSP) and moderate lipophilicity (2 > cLogP > 4). Evaluation of the [11C]3- methoxy derivatives of MPEP (IC50, 2.0 nM; cLogP, 3.0; 42) and PEPy (IC50, 1.5 nM; cLogP, 2.25; 43) with PET in rat and monkey, showed that these radiotracers have acceptable penetration into brain (~ 550-650 %SUV), but that radioactivity clears rapidly from all brain regions giving at most only a small short-lived receptor-specific signal in monkey, as detected through pre-blocking experiments.66 A 11C labeled isomer of 3-methoxy-MTEP, 2-(2-(3-methoxyphenyl)- ethynyl)-4-methylthiazole (IC50, 5 nM; cLogP, 2.61; 44) and [11C]3- methyl-MTEP (IC50, 3 nM; cLogP, 2.4; 45) showed similar behavior,67 as did [18F]6-fluoro-MPEPy (IC50, 2.8 nM; cLogP, 2.65; 46). Finally, a candidate radiotracer from a distinctly different structural class, namely [11C](2-(4-ethyl-3-methoxyphenyl)-benzo[d]oxazole) (IC50, 3 nM; cLogP, 2.79; YP 426, 47), also showed excellent brain penetration, but again fast washout from all regions.