Evaluation of [18F]fluoroxanomeline {5-{4-[(6-[18F]fluorohexyl)oxy]-1 2,5-thiadiazol-3-yl}-1-methyl-1,2,3,6-tetrahydropyridine}

Introduction: We set out to develop a muscarinic MI-selective agonist (based on the structure of the functionally MI-selective xanomeline) that could be radiolabeled with fluorine-18 for use as an imaging agent for positron emission tomography. Methods: The radiochemical synthesis was achieved, employing the arts of organic and radiochemical syntheses. Binding selectivity studies employed biodistribution studies, using autoradiography and/or tissue dissection, in wild-type or muscarinic receptor knockout mice. Results: [F-18]Fluoroxanomeline shows rather uniform uptake in all mouse brain regions and high specific binding, with a brain-to-blood ratio of 32 at 60 min postinjection. In addition, the specific binding is demonstrated by a 58% to 75% decrease in brain uptake upon coinjection with 5 nmol of unlabeled fluoroxanomeline or xanomeline. Brain uptake studies with [H-3]xanomeline in muscarinic knockout mice show decreased uptake in M1 (17-34%) and M2 (2-20%) knockout mice compared with control. However, statistical significance was observed in only a few regions. Comparison of [F-18]fluoroxanomeline in knockout mice showed no difference in M I or M4 knockout mice but a general decrease in M2 (2-24%) knockout mice. The decrease of [F-18]fluoroxanomeline uptake in M2 knockout mice reached statistical significance in brain stem, cerebellum, frontal cortex, hippocampus, inferior colliculus and superior colliculus. Conclusion: Although xanomeline displays highly selective MI agonist activity in functional assays, little selectivity for muscarinic subtype binding was observed for xanomeline or its fluorine-containing analogue, fluoroxanomeline. This emphasizes the lack of correlation between functional selectivity and binding selectivity. (c) 2007 Elsevier Inc. All rights reserved.