RESOLUTION, IN-VITRO AND IN-VIVO EVALUATION OF FLUORINE-18-LABELED ISOMERS OF 1-AZABICYCLO[2.2.2]OCT-3-YL FLUOROPENT-5-YL)-ALPHA-HYDROXY-ALPHA-PHENYLACETATE (FQNPE) AS NEW PET CANDIDATES FOR THE IMAGING OF MUSCARINIC-CHOLINERGIC RECEPTOR

l-Azabicyclo[2.2.2]oct-3-yl fluoropent-5-yl)-alpha-hydroxy-alpha-pheny lacetate (FQNPe, 2), an analogue of 1-azabicyclo[2.2.2]oct-3-yl alpha, alpha-(diphenyl)-alpha-hydroxyacetate (QNB), was resolved into its fou r stereoisomers. In vitro binding assays of the stereoisomers of 2 dem onstrated that while the (S,S)-isomer did not have significant recepto r binding, the other stereoisomers of 2 bound with high affinity to th e various mAChR subtypes [K-i, nM: m1, (R,R), 0.33; (R,S), 1.4; (S,R), 3.8; m2, (R,R), 0.1; (R,S), 4.2; (S,R), < 75% binding; m3, (R,R), 0.3 4; (R,S), 3.1; (S,R), 7.6]. The (R,R)- and (R,S)stereoisomers of 2 wer e radiolabeled with fluorine-18 via a two step procedure in radiochemi cal yields of 12-21% (n=2) and 9% (decayed corrected to beginning of s ynthesis), respectively. In vivo biodistribution studies demonstrated significant uptake of [F-18]-(R,R)-2 in cerebral mAChR-rich regions of rat brains up to 3 h post injection. Low accumulation of fluorine-18 in the bone indicated that [F-18]-(R,R)-2 displayed significant in viv o stability. In contrast. [F-18]-(R,S)-2 demonstrated rapid washout fr om all cerebral regions. Preinjection of (R)-QNB (3 mg/kg) 1 h prior t o the injection of [F-18]-(R,R)-2 blocked the uptake of activity in ce rebral regions by approximately 90% while the preinjection of haloperi dol (3 mg/kg) 1 h prior to the injection of [F-18]-(R;R)2 demonstrated no statistically significant effect on the binding of the radiotracer . An ex vivo metabolic study utilizing [F-18]-(R,R)-2 demonstrated tha t greater than 96% of the organic soluble radioactivity which localize d in the brain and heart at 1 h post-injection migrated on TLC with th e same mobility as the parent. Although [F-18]-(R,R)-2 did not demonst rate a desired in vitro or in vivo mAChR subtype selectivity, these re sults suggest that the introduction of a fluoroalkyl group in various benzylic analogues of QNB is an attractive radiolabeling moiety for fu rther evaluation in the design of selective PET mAChR imaging ligands.