Evaluation of 1-azabicyclo[2.2.2]oct-3-yl α-fluoroalkyl-α-hydroxy-α-phenylacetates as potential ligands for the study of muscarinic receptor density by positron emission tomography☆

Add time:08/19/2019    Source:sciencedirect.com

Both 1-azabicyclo[2.2.2]oct-3-yl α-(1-fluoroeth-2-yl)-α-hydroxy-α-phenylacetate (FQNE, 5) and 1-azabicyclo[2.2.2]oct-3-yl α-(1-fluoropent-5-yl)-α-hydroxy-α-phenylacetate (FQNPe, 6) were prepared and evaluated as potential candidates for the determination of muscarinic cholinergic receptor (mAChR) density by positron emission tomography (PET). The results of in vitro binding assays demonstrated that although both 5 and 6 had high binding affinities for m1 and m2 mAChR subtypes, 6 displayed a higher affinity (nM, m1; KD, 0.45, m2; KD, 3.53) as compared to 5 (nM, m1 KD, 12.5, m2; KD, 62.8). It was observed that pretreatment of female Fisher rats with either 5 or 6 prior to the i.v. administration of Z-(−)(−)-[131I]-IQNP, a high-affinity muscarinic ligand, significantly blocked the uptake of radioactivity in the brain and heart measured 3 h postinjection of the radiolabeled ligand. These new fluoro QNB analogues represent important target ligands for evaluation as potential receptor imaging agents in conjunction with PET.

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