Quantification of human nicotinic acetylcholine receptors with ¹²³I-5IA SPECT

Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in the human brain, especially the α₄β₂ subtype of nAChR. The cholinergic systems have roles in various neurophysiologic functions, such as learning, memory, and cognition, whereas normal aging and neurodegenerative diseases have been associated with changes in nAChRs. Recently, 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5IA) has been synthesized as a radioligand for imaging nAChRs with SPECT. ¹²³I-5IA shows higher affinity toward the nAChR α₄β₂ subtype, enhanced receptor subtype selectivity, good safety, and low nonspecific binding. Methods: In this study, a SPECT quantitative study of human nAChRs binding with ¹²³I-5IA was conducted in healthy volunteers. An arterial input function was obtained for each subject and a 2-compartment model was used to determine the kinetic parameters of ¹²³I-5IA using data from a 6-h scan. The distribution volume (V_T) (mL/mL), which is related to the number of unoccupied binding sites in the brain, was calculated and values were compared with results of a graphical analysis (Logan plot, V_LG). Results: Analysis of the unmetabolized compound showed a high parent fraction of ¹²³I-5IA in plasma. The results from the 2-compartment model analysis showed high V_T values for the thalamus; moderate values for the brain stem, cerebellum, and basal ganglia; and low values for the cortical regions. Good agreement was observed between V_T values and results of autoradiographic experiments done in vitro for nAChR density in human brain. A high correlation index was observed between distribution volumes from model and graphical analyses. Conclusion: Our results indicated that ¹²³I-5IA SPECT is suitable for the quantification of nAChRs in human brain.