Influence of acetylcholine levels on the binding of a SPECT nicotinic acetylcholine receptor ligand [¹²³I]5‐I‐A‐85380

Abstract

Although in vitro theory indicates that ligand binding is sensitive to competition with neurotransmitters, only some imaging ligands have shown such competition in vivo. The purpose of this study was to determine whether increases in acetylcholine (ACh) levels induced by an acetylcholinesterase inhibitor, physostigmine, inhibit in vivo binding of [(123)I]5-iodo-3-(2(S)-2-azetidinyl-methoxy) pyridine (5-I-A-85380), a single photon emission computed tomography ligand for the high-affinity type nicotinic ACh receptor (nAChR). Baboons were used for seven studies with a bolus plus constant infusion equilibrium paradigm. After achieving equilibrium at 5 h, physostigmine (0.02 (n = 1), 0.067 (n = 3), and 0.2 (n = 3) mg/kg) was administered intravenously and data were acquired for up to 8 h. To confirm equilibrium conditions, [(123)I]5-I-A-85380 plasma levels were measured in four studies, including all studies with 0.2 mg/kg physostigmine. Prior to physostigmine administration, thalamic activities were stable, with changes of 1.1%/h or less, except in one study with a gradual increase of 4.2%/h. Thalamic activities were decreased by 15% in one study with 0.067 mg/kg and 14-17% in all studies with 0.2 mg/kg physostigmine administration (P = 0.009). In these studies with 0.2 mg/kg physostigmine administration, [(123)I]5-I-A-85380 plasma levels showed a transient or a sustained increase after physostigmine administration that would have increased thalamic activities. These results suggest that elevated ACh levels induced by physostigmine can effectively compete in vivo with [(123)I]5-I-A-85380 binding at nAChRs. However, decreased thalamic activities could have been caused by other mechanisms, including internalization of the receptor with an associated decreased affinity for radioligand.

123I-5-IA-85380 SPECT Imaging of Nicotinic Acetylcholine Receptor Availability in Nonsmokers: Effects of Sex and Menstrual Phase

“…Although a finding of no sex difference in b 2 -nAChR availability in nonsmokers does not preclude a sex difference in b 2 -nAChR availability in smokers, it does raise the question of whether availability of b 2 -nAChRs is involved in the sex differences in tobacco-smoking behavior, such as differences in quitting smoking and in response to nicotine replacement therapy. Although 123 I-5-IA SPECT measures the availability of b 2 -nAChR, this measure may be confounded by occupancy of the receptor by endogenous acetylcholine (46). However, no reports of sex differences in endogenous acetylcholine levels could be found, and plasma acetylcholine does not vary in women with gonadal hormone levels (47).…”

A‐85380: A Pharmacological Probe for the Preclinical and Clinical Investigation of the α4β2 Neuronal Nicotinic Acetylcholine Receptor

“…In vivo studies in both the baboon and human have demonstrated the potential usefulness of the ligand in the investigation of nAChRs (20,22). Similar to 2-[ 18 F]F-A-85380, compounds that can increase endogenous levels of acetylcholine, such as physostigmine, can effectively compete with [ 123 I]5-iodo-A-85380 for binding (19).…”

Pharmacokinetic Modeling and [123I]5-IA-85380 Single Photon Emission Computed Tomography Imaging in Baboons: Optimization of Dosing Regimen for ABT-089

“…123 I]5-IA binding patterns (Fujita et al, 2003a). ABT-089 has been shown to improve behavioral performance across a range of cognitive domains in animals (Decker et al, 1997) but has demonstrated a mixed picture of ABT-089 (mg/kg, iv) at ASPET Journals on May 9, 2018 jpet.aspetjournals.org efficacy in humans (Wilens et al, 2006;Bain et al, 2009;Gault et al, 2009).…”

“…123 I]5-IA seems to predominantly label the ␣ 4 ␤ 2 * subtype and that radioligand uptake can be displaced by endogenous acetylcholine as well as by nicotine and cytisine (Fujita et al, 2003a).…”

“…In particular, 5-[ ]5-IA) has been extensively used as a SPECT radioligand for nAChRs. As shown by Fujita et al (2003a), [ 123 I]5-IA rapidly penetrates the blood-brain barrier with low nonspecific binding and minimal toxicity. In addition, the same authors have also found that […”