Synthesis and Evaluation of N-[¹¹C]Methylated Analogues of Epibatidine as Tracers for Positron Emission Tomographic Studies of Nicotinic Acetylcholine Receptors

Abstract

Four halogen-substituted analogues of N-methylepibatidine, a nicotinic acetylcholine receptor (nAChR) ligand, were synthesized. They were (+/-)-exo-N-methyl-2-(2-halogeno-5-pyridyl)-7-azabicyclo[2. 2.1]heptanes, where halogeno = F (1a), Cl (2a), Br (3a), I (4a). (+/-)-N-Ethylepibatidine (2b) also was synthesized. The compounds 1a, 2a, 3a, and 4a and their corresponding normethyl analogues 1, 2, 3, and 4 inhibited the in vitro binding of [3H]epibatidine to nAChRs to a similar degree, with affinities in the 27-50 pM range. The binding affinity of N-ethylepibatidine (2b), however, was substantially lower. The N-[11C]methyl derivatives of 1, 2, and 3 were synthesized from high-specific radioactivity [11C]methyl iodide using a high-temperature/high-pressure technique. The corresponding radiolabeled compounds [11C]1a, [11C]2a, and [11C]3a were administrated to mice intravenously. The pattern of regional distribution of the three tracers in the mouse brain following intravenous administration matched those of [3H]epibatidine, [3H]norchloroepibatidine, and (+/-)-exo-2-(2-[18F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([18F]FPH), which are highly specific nAChR probes. The initial brain uptake of the 11C analogues and the acute toxicity of the corresponding authentic nonlabeled compounds appeared to be related to their lipophilicity.

Effects of Pyridine Ring Substitutions on Affinity, Efficacy, and Subtype Selectivity of Neuronal Nicotinic Receptor Agonist Epibatidine

“…This has been jpet.aspetjournals.org a problem with other epibatidine analogs. Halogen-substituted and methylated analogs of epibatidine have been reported to produce fewer toxicities in rodents (Badio et al, 1997;Horti et al, 1998); however, the reduction in toxic effects seen in these studies was not sufficient to ensure safe therapeutic/toxicity ratios. Epiboxidine, a methylisoxazole analog of epibatidine has also been reported to produce fewer toxicities than epibatidine in mice (Badio et al, 1997).…”

“…Epibatidine is reported to exhibit high-potency analgesic activity with a longer duration of action than nicotine (Qian et al, 1993;Rogers and Iwamoto, 1993;Badio and Daly, 1994), and epibatidine analogs are currently under investigation as nonopioid analgesics. However, epibatidine is reported to produce various toxicities in rodents, including increased heart rate, motor incoordination, and seizure (Sullivan et al, 1994;Bonhaus et al, 1995;Horti et al, 1998). The toxicity of epibatidine may arise from its capacity to activate many different neuronal nAChR subtypes.…”

Central Nicotinic Receptors: Structure, Function, Ligands, and Therapeutic Potential

“…[75] Modifications on the basic nitrogen of 18 are not well tolerated: only N-methylation gives compounds with comparable affinity, whereas the N-ethyl analogue showed an affinity 500 times lower. [76] It is not surprising that compounds 21 showed much lower affinity than 18; however their K i values were still in the nanomolar range. [77] It is a pity that these compounds have been tested only as a mixture of isomers, and their functional activity has not been measured, as it is known that Nmethylation of 18 introduces some enantioselectivity in functional tests on a4b2, a3b4, and a7 receptors.…”

5-Iodo-A-85380, an α4β2 Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors

“…In contrast to ␣4␤2 nAChRs, nAChRs containing ␣3 and ␤4 subunits, possibly in combination with ␣5 subunits, are distributed mostly in the peripheral nervous system and adrenal glands (Holladay et al, 1997). Therefore, high affinity for the latter receptors could contribute to the untoward cardiovascular effects of epibatidine and its analogs (Molina et al, 1997;Horti et al, 1998) and might limit the use of epibatidine-based compounds for imaging nAChRs in human subjects.…”