Evaluation of [(18)F]-(-)-norchlorofluorohomoepibatidine ([(18)F]-(-)-NCFHEB) as a PET radioligand to image the nicotinic acetylcholine receptors in non-human primates.

INTRODUCTION: The aims of the present study were to develop an optimized microfluidic method for the production of the selective nicotinic acetylcholine α4ß2 receptor radiotracer [(18)F]-(-)-NCFHEB ([(18)F]-Flubatine) and to investigate its receptor binding profile and pharmacokinetic properties in rhesus monkeys in vivo. METHODS: [(18)F]-(-)-NCFHEB was prepared in two steps, a nucleophilic fluorination followed by N-Boc deprotection. PET measurements were performed in rhesus monkeys including baseline and preblocking experiments with nicotine (0.24 mg/kg). Radiometabolites in plasma were measured using HPLC. RESULTS: [(18)F]-(-)-NCFHEB was prepared in a total synthesis time of 140 min. The radiochemical purity in its final formulation was >98% and the mean specific radioactivity was 97.3 ± 16.1 GBq/µmol (n = 6) at end of synthesis (EOS). In the monkey brain, radioactivity concentration was high in the thalamus, moderate in the putamen, hippocampus, frontal cortex, and lower in the cerebellum. Nicotine blocked 98-100% of [(18)F]-(-)-NCFHEB specific binding, and the non-displaceable distribution volume (VND) was estimated at 5.9 ± 1.0 mL/cm(3) (n = 2), or 6.6 ± 1.1 mL/cm(3) after normalization by the plasma free fraction fP. Imaging data are amenable to kinetic modeling analysis using the multilinear analysis (MA1) method, and model-derived binding parameters display good test-retest reproducibility. In rhesus monkeys, [(18)F]-(-)-NCFHEB can yield robust regional binding potential (BPND) values (thalamus = 4.1 ± 1.5, frontal cortex = 1.2 ± 0.2, putamen = 0.96 ± 0.45, and cerebellum = 0.10 ± 0.29). CONCLUSION: An efficient microfluidic synthetic method was developed for preparation of [(18)F]-(-)-NCFHEB. PET examination in rhesus monkeys showed that [(18)F]-(-)-NCFHEB entered the brain readily and its regional radioactivity uptake pattern was in accordance with the known distribution of α4ß2 receptors. Estimated non-displaceable binding potential (BPND) values in brain regions were better than those of [(18)F]2-FA and comparable to [(18)F]AZAN. These results confirm previous findings and support further examination of [(18)F]-(-)-NCFHEB in humans.

Neuroimaging insights into the role of cortical GABA systems and the influence of nicotine on the recovery from alcohol dependence.

This paper reviews evidence suggesting that nicotine and tobacco smoke profoundly modulate the effects of alcohol on γ-aminobutyric acid (GABA) neuronal function, specifically at the GABA(A)-benzodiazepine receptor (GABA(A)-BZR). The focus of this paper is on recent neuroimaging evidence in preclinical models as well as clinical experiments. First, we review findings implicating the role of alcohol at the GABA(A)-BZR and discuss the changes in GABA(A)-BZR availability during acute and prolonged alcohol withdrawal. Second, we discuss preclinical evidence that suggests nicotine affects GABA neuronal function indirectly by a primary action at neuronal nicotinic acetylcholine receptors. Third, we show how this evidence converges in studies that examine GABA levels and GABA(A)-BZRs in alcohol-dependent smokers and nonsmokers, suggesting that tobacco smoking attenuates the chemical changes that occur during alcohol withdrawal. Based on a comprehensive review of literature, we hypothesize that tobacco smoking minimizes the changes in GABA levels that typically occur during the acute cycles of drinking in alcohol-dependent individuals. Thus, during alcohol withdrawal, the continued tobacco smoking decreases the severity of the withdrawal-related changes in GABA chemistry. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Synthesis of 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles and their in vitro and in vivo evaluation as imaging agents for amyloid plaque.

A series of novel 5- and 6-substituted 2-(4-dimethylaminophenyl)-1,3-benzoxazoles was synthesized and their potential as imaging probes for Alzheimer's Disease (AD)-related amyloid plaque was evaluated in vitro and in vivo. In vitro binding affinities for Abeta1-40 peptide of several of these compounds were in the low-nanomolar range . The lowest K(i) of 9.3nM was found for N-(2-(4-(dimethylamino)phenyl)-1,3-benzoxazol-5-yl)-4-iodobenzamide (1e). Its (123)I-radiolabeled form ([(123)I]1e) was subsequently prepared by iododestannylation of the corresponding tributylstannyl precursor and evaluated in vivo in a baboon model using SPECT imaging. Contrary to our expectations, 1e did not cross the blood-brain barrier (BBB) to any significant extent.

[123I]5-IA-85380 SPECT imaging of beta2-nicotinic acetylcholine receptor availability in the aging human brain.

Human postmortem studies have reported decreases with age in high-affinity nicotine binding in brain. We have been investigating in vivo the availability of the beta(2)-containing nicotinic acetylcholine receptor (beta(2)-nAChR) in healthy nonsmokers (18-85 years of age) using [(123)I]5-IA-85380 SPECT imaging. Age and regional beta(2)-nAChR availability (V(T)(,)) have been observed to be inversely correlated in all brain regions analyzed, with decline ranging from 21% (cerebellum) to 36% (thalamus), or by up to 5% per decade of life. Preliminary results have confirmed postmortem reports of age-related decline in high-affinity nicotine binding with age and may elucidate the role of beta(2)-nAChRs in the cognitive decline associated with aging.