Pharmacological evaluation of a Br‐76 analog of epibatidine: A potent ligand for studying brain nicotinic acetylcholine receptors

Abstract

[(76)Br]-Norchlorobromoepibatidine ([(76)Br]BrPH) is a specific and high affinity radioligand for the nicotinic acetylcholine receptors (nAChRs). In vitro, on rat thalamus membranes [(76)Br]BrPH bound to two sites with apparent affinities of 8 pM and 3 nM. The density of binding sites were 1.9 and 70 fmol/mg protein, respectively. In vivo, in biodistribution and autoradiographic studies in rats the regional distribution of [(76)Br]BrPH paralleled the neuroanatomical localization of nAChRs. Two hours postinjection, the highest concentration in the brain was found in thalamus and colliculi (4% ID/g). Competition experiments with specific nicotinic, muscarinic, dopaminergic, and serotoninergic drugs confirmed that the in vivo binding of [(76)Br]BrPH was consistent with neuronal nicotinic receptors. PET imaging of [(76)Br]BrPH in baboon demonstrated a rapid and high uptake in the brain. Peak uptake occurred at 30-40 min for the thalamus. Due to the constant washout in the cerebellum, the thalamus to cerebellum ratio was 5 at 2 h postinjection. Subcutaneous injection of cytisine (1 mg/kg), 3 h postinjection of [(76)Br]BrPH reduced the radioactivity concentration in thalamus and cortex by 58 and 50%, respectively, as observed 1 h later. Cytisine pretreatment (5 mg/kg s.c.) inhibited completely the radioligand accumulation in the thalamus. Chronic MPTP pretreatment resulted in reduction of [(76)Br]BrPH uptake in all brain regions except in cerebellum. These preliminary results suggest that [(76)Br]BrPH has the potential to be a useful radioligand for studying the pharmacology of nicotinic acetylcholine receptors in preclinical experiments.

Single photon emission computed tomography experience with (S)‐5‐[123I]iodo‐3‐(2‐azetidinylmethoxy)pyridine in the living human brain of smokers and nonsmokers

“…Although [ 11 C]( S )-(−)-nicotine has been used in the past in an attempt to visualize human nAChRs, this radiotracer suffers from a high degree of non-specific binding that makes it far from ideal as a specific nAChR probe (Scheffel et al, 2000; Villemagne et al, 1998). [ 79 Br]Norchlorobromoepibatidine (Kassiou et al, 2002) and [ 18 F]norchloro-fluoro-homoepibatidine are being evaluated as a specific high-affinity radioligands for nAChRs (Brust et al, 2008). However, the toxic effects of epibatidine and its congeners may prohibit its use in humans (Horti et al, 2000; Rueter et al, 2006; Scheffel et al, 2000).…”

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

“…Other PET-labeled epibatidine analogs have also been reported, including [ 76 Br]norchlorobromoepibatidine [127] (Fig. 14).…”

“…In both blocking and displacement studies, subcutaneous cytisine reduced the specific binding in all regions of the brain except the cerebellum. An MPTP-treated baboon showed only half of the uptake in the thalamus, with the uptake in cortex and striatum being similar to that in the cerebellum [127].…”

Synthesis of [18F]3‐[1‐(3‐fluoropropyl)‐(S)‐pyrrolidin‐2‐ylmethoxy]pyridine ([18F]NicFP): a potential α4β2 nicotinic acetylcholine receptor radioligand for PET

“…Several epibatidine analogues have been synthesized and labelled with carbon-11, fluorine-18, bromine-76, and iodine-123. [8][9][10][11] More recently, a series of 3-pyridyl ether compounds that are more selective for the a4b2 subtype has been reported. One of the first derivatives, A-85380, has an affinity comparable with epibatidine and has been labelled with iodine-123 12,13 and fluorine-18.…”