Potential Receptor Imaging Agents Research Articles

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

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 m 1 and m 2 mAChR subtypes, 6 displayed a higher affinity (nM, m 1; K D, 0.45, m 2; K D, 3.53) as compared to 5 (nM, m 1 K D, 12.5, m 2; K D, 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.

In vitro and ex vivo evaluation of cyclic aminoalkyl benzilates as potential emission tomography ligands for the muscarinic receptor

A series of muscarinic antagonists were screened as potential receptor imaging agents. (+)2α-tropanyl benzilate (TRB), N-methyl-4-piperidyl benzilate (NMPB) and several analogs amenable to labeling with positron emitting isotopes were evaluated for muscarinic binding to mouse brain tissue in vitro and ex vivo using [ 3H]quinuclidinyl benzilate as the probe. The in vitro assay directly compared the innate binding affinities of the compounds. The rank order of binding (IC 50) was TRB (0.7 nm), QNB (0.8 nm), scopolamine (1.3 nm) and NMPB (1.6 nm). The ex vivo assay was used to gain information regarding the pharmacokinetics and brain penetration of the compounds in live animals. Ex vivo results demonstrated that TRB was rapidly taken up into the brain and was equipotent with QNB in occupying muscarinic binding sites at early time points, but TRB binding decreased twice as fast over time as QNB binding. The results suggest TRB would be a good candidate for radiolabeling and further study.