Synthesis and evaluation of novel radioligands for positron emission tomography imaging of metabotropic glutamate receptor subtype 1 (mGluR1) in rodent brain

Article abstract of DOI:10.1021/jm201590g

We designed three novel positron emission tomography ligands, N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-[ ¹¹C]methoxy-N-methylbenzamide ([¹¹C]6), 4-[ ¹⁸F]fluoroethoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1, 3-thiazol-2-yl]-N-methylbenzamide ([¹⁸F]7), and 4-[ ¹⁸F]fluoropropoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1, 3-thiazol-2-yl]-N-methylbenzamide ([¹⁸F]8), for imaging metabotropic glutamate receptor type 1 (mGluR1) in rodent brain. Unlabeled compound 6 was synthesized by benzoylation of 4-pyrimidinyl-2-methylaminothiazole 10, followed by reaction with isopropylamine. Removal of the methyl group in 6 gave phenol precursor 12 for radiosynthesis. Two fluoroalkoxy analogues 7 and 8 were prepared by reacting 12 with tosylates 13 and 14. Radioligands [ ¹¹C]6, [¹⁸F]7, and [¹⁸F]8 were synthesized by O-[¹¹C]methylation or [¹⁸F]fluoroalkylation of 12. Compound 6 showed high in vitro binding affinity for mGluR1, whereas 7 and 8 had weak affinity. Autoradiography using rat brain sections showed that [ ¹¹C]6 binding is aligned with the reported distribution of mGluR1 with high specific binding in the cerebellum and thalamus. PET study with [ ¹¹C]6 in rats showed high brain uptake and a similar distribution pattern to that in autoradiography, indicating the usefulness of [ ¹¹C]6 for imaging brain mGluR1.