Imaging Changes in Synaptic Acetylcholine Availability in Living Human Subjects

In vivo estimation of β2-nicotinic acetylcholine receptor availability with molecular neuroimaging is complicated by competition between the endogenous neurotransmitter acetylcholine and the radioligand 123I-3-[2(S)-2-azetidinylmethoxy]pyridine (123I-5-IA). We examined whether binding of 123I-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 123I-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 123I-5-IA for binding to β2-nicotinic acetylcholine receptor. Additional validation of this paradigm is warranted, but it may be used to interrogate changes in extracellular acetylcholine.