Pharmacology, toxicology, and radiation dosimetry evaluation of [¹²³I]5‐I‐A‐85380, a radioligand for in vivo imaging of cerebral neuronal nicotinic acetylcholine receptors in humans

Abstract

[123 I]5-I-A-85380, which selectively binds to a4b2 nicotinic acetylcholine receptors, may be a suitable single photon emission computed tomography (SPECT) ligand for imaging nicotinic receptors in the human brain. In a mutagenicity study, 5-I-A-85380 produced positive effects in one of five bacterial strains in the bacterial reverse mutation assay only with metabolic activation. The ED 50 for 5-I-A-85380 to elicit tonicclonic convulsions in mice, 7.1 mmol/kg, i.v., was five times that of nicotine (ED 50 ¼ 1.4 mmol/kg, i.v.). A 2-day acute toxicity study (0.03-150 nmol/kg, i.v.) and a 14-day chronic toxicity study (0.3-30 nmol/kg, s.c.) in mice revealed no evidence of gross pathology or histopathological changes. Biodistribution and dosimetry studies revealed that the urinary bladder wall and the thyroid gland were the critical organs with respect to radiation exposure. In unanesthetized rats, 5-I-A-85380 (5.2-174 nmol/kg, i.v.) and nicotine (20-400 nmol/kg, i.v.) produced similar increases in systolic and diastolic blood pressure, heart rate, and locomotor activity. Doses of 5-I-A-85380 that elevated blood pressure and heart rate by 10% ranged from 5-10 nmol/kg, i.v. The highest doses tested, which produced near maximal increases in blood pressure and heart rate, did not affect the PR, QRS, or QTc intervals of the electrocardiogram. Based on these preclinical data, initial SPECT imaging studies in humans (Fujita et al. [2002] Eur J Nucl Med 29:183-190) used a mass dose of 8.6 pmol/kg [ 123 I]5-I-A-8380, estimated to be 1/580th of the dose that elevates blood pressure and heart rate by 10%. Importantly, no clinical pharmacological effects were observed. Drug Dev.

Temporal Change in Human Nicotinic Acetylcholine Receptor After Smoking Cessation: 5IA SPECT Study

“…123 I-5IA is a nAChR imaging probe that has extremely high selectivity and specificity for the a4b2 subunit of nAChRs in rodent (inhibition constant 5 0.37 nM) (15) and primate brain in vivo (16), with relatively low acute toxicity (effective dose equivalent 5 30 mSv/MBq) (17,18). Moreover, we have developed the methodology for the quantification of nAChRs in human brain using 123 I-5IA and SPECT (19).…”

5-123I-A-85380 binding to the α4β2-nicotinic receptor in mild cognitive impairment

“…It is well tolerated and whole body distribution and dosing data have been reported (Fujita, et al, 2002, Vaupel, et al, 2003. Age and sex related changes of plasmalevels and receptor binding have been characterised , Mitsis, et al, 2008.…”

“…Analysis for regionally specific effects of 5-IA distribution was done with SPM2 (Wellcome Department of Imaging Neuroscience, University College London, 2003) in conjunction with MATLAB version 7.2 (The MathWorks, Inc. Natick MA, USA).…”

Pharmacological and Toxicological Evaluation of 2-Fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-F-A-85380), a Ligand for Imaging Cerebral Nicotinic Acetylcholine Receptors with Positron Emission Tomography

“…Previously, ␣4␤2* nAChRs were imaged in the human brain using SPECT and (Abreo et al, 1996) and represent a major advancement in the noninvasive imaging of nAChRs over 11 C-labeled nicotine (Chefer et al, 1998;Musachio et al, 1998;Vaupel et al, 1998Vaupel et al, , 2003Horti et al, 1999).…”

“…Tremors, forepaw treading, transfer arousal, motor incoordination, changes in respiration, and convulsions constituted the most useful nonparametric measures. A detailed description of the battery has been published (Vaupel et al, 2003). To accommodate the rapid kinetics resulting from intravenous administration, the test battery was completed within 6 min.…”