Imaging changes in synaptic acetylcholine availability in living human subjects

Abstract

In vivo estimation of β(2)-nicotinic acetylcholine receptor availability with molecular neuroimaging is complicated by competition between the endogenous neurotransmitter acetylcholine and the radioligand (123)I-3-[2(S)-2-azetidinylmethoxy]pyridine ((123)I-5-IA). We examined whether binding of (123)I-5-IA is sensitive to increases in extracellular levels of acetylcholine in humans, as suggested in nonhuman primates.

Methods: Six healthy subjects (31 ± 4 y) participated in a (123)I-5-IA SPECT study. After baseline scans, physostigmine (1-1.5 mg) was administered intravenously over 60 min, and 9 additional scans were obtained.

Results: We observed a significant reduction in the total volume of distribution after physostigmine administration (29% ± 17% in the cortex, 19% ± 15% in the thalamus, 19% ± 15% in the striatum, and 36% ± 30% in the cerebellum; P < 0.05). This reduction reflected a combination of a region-specific 7%-16% decrease in tissue concentration of tracer and a 9% increase in plasma parent concentration.

Conclusion: These data suggest that increases in acetylcholine compete with (123)I-5-IA for binding to β(2)-nicotinic acetylcholine receptor. Additional validation of this paradigm is warranted, but it may be used to interrogate changes in extracellular acetylcholine.

Figure 1

The first point in each graph represents baseline data obtained starting 6 h after beginning tracer infusion when a state of equilibrium is achieved, and provided the baseline specific binding. Following completion of the baseline scans, physostigmine was administered I.V. (1.0–1.5 mg over 1 h, arrow). At the onset of the physostigmine infusion, scanning was resumed for up to 9 h. Bars represent standard error of the mean (SEM). A. Plasma [¹²³I]5-IA concentration (kBq/mL) (total parent) measured during [¹²³I]5-IA constant infusion in healthy volunteers. Following physostigmine administration there was a significant 8% increase in mean plasma [¹²³I]5-IA concentration as compared to before physostigmine administration. B. Tissue [¹²³I]5-IA concentration (kBq/cc) in thalamus (circles), striatum (triangles), cortex (open circles), and cerebellum (squares) measured during [¹²³I]5-IA constant infusion. We observed 7–15% region specific decrease in [¹²³I]5-IA tissue concentration after physostigmine challenge. C. [¹²³I]5-IA total volume of distribution (V_T/f_p) in thalamus (circles), striatum (triangles), cortex (open circles), and cerebellum (squares) measured during [¹²³I]5-IA constant infusion. V_T/f_p values measured after the physostigmine infusion were significantly reduced (14–18% region specific) compared to the baseline values. D. [¹²³I]5-IA specific binding (BP_f) in thalamus (circles), striatum (triangles), cortex (open circles), and cerebellum (squares) measured during [¹²³I]5-IA constant infusion. BP_f values measured after the physostigmine infusion were significantly reduced (19–36% region specific) compared to the baseline values.

Figure 2

A. β₂-nAChR availability (V_T/f_P) before (shaded bars) and after (solid bars) physostigmine injection for each subject. Thalamus: Percent displacement of 5-IA for subjects 1–6 were −7%, −22%, −14%, −22%, −35%, −0%, respectively. Striatum: Percent displacement of 5-IA for subjects 1–6 was −8%, −20%, −18%, −20%, −25%, −4%, respectively. Cortex: Percent displacement of 5-IA for subjects 1–6 were −9%, −25%, −18%, −26%, −30%, −2%, respectively. Cerebellum: Percent displacement of 5-IA for subjects 1–6 was −12%, −20%, −18%, −23%, −28%, 0%, respectively. B. Specific radioligand binding (V_s/f_P) before (shaded bars) and after (solid bars) physostigmine injection for each subject. Thalamus: Percent displacement of 5-IA for subjects 1–6 were −8%, −25%, −17%, −25%, −41%, 0%, respectively. Striatum: Percent displacement of 5-IA for subjects 1–6 was −10%, −27%, −24%, −26%, −34%, +5%, respectively. Cortex: Percent displacement of 5-IA for subjects 1–6 were −13%, −40%, −29%, −36%, −50%, −6%, respectively. Cerebellum: Percent displacement of 5-IA for subjects 1–6 was −17%, −90%, − 35%, −32%, −40%, −1%, respectively.