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: K_d 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.