Methodology Poster Abstracts

Background: Competition between neurotransmitter and radioligands has provided a very useful method to assess synaptic changes in dopamine, but this approach has been slow to extend to other neurotransmitter system. Previously, Fujita and colleagues showed that the high affinity beta2-nicotinic acetylcholine receptor (b2-nAChR) radioligand [I]5-IA85380 (5-IA) may be sensitive to extracellular increases in ACh in baboons; 1 however, such an examination in humans has lagged. Given that acetylcholine is one of the major neurotransmitters in the brain and has been implicated in the psychiatric and medical illnesses, we developed a paradigm to interrogate the ACh system in vivo via use of 5-IA SPECT imaging and physostigmine, a centrally-acting acetylcholinesterase inhibitor. Methods: Six healthy subjects (3 men, 3 women; 31±4.1 yrs) participated in one 5-IA SPECT study. 5-IA was administered as a bolus plus constant infusion (B/I 7.0 h); total injected dose was 390.2±13.2 MBq. After three 30-min baseline scans at 6-8 h post infusion, physostigmine (1-1.5 mg) was administered IV over 60 min, and nine additional 30-min scans were collected during the next 6 h. The outcome measure was BPF (specific volume of distribution), calculated as VT/fp (estimated receptor availability) minus VND/fp (nondisplaceable binding; previously estimated in a smoking to satiety paradigm). Results: We observed a significant reduction in BPF after physostigmine administration (25±15% reduction in cortical regions, 15±11% thalamus (Figure 1), 16±14% in striatum, and 35±34% in cerebellum; p < .05). This effect reflected a combination of a significant decrease in tissue concentration of 5-IA (7-16% region specific, p < .05) and a significant increase in plasma parent concentration (8%, p < .05). Conclusions: These data suggest that physostigmineinduced increases in extracellular ACh might compete with 5-IA for binding to b2-nAChRs in humans, although other mechanisms, such as a direct effect of physostigmine on nicotinic acetylcholine receptors, should be ruled out. Additional validation of this paradigm is warranted, but we suggest that nicotinic imaging could be used to interrogate changes in synaptic ACh.