PET Imaging of Nicotinic Acetylcholine Receptors in Baboons with 18F-AZAN, a Radioligand with Improved Brain Kinetics
PET Imaging of Nicotinic Acetylcholine Receptors in Baboons with 18F-AZAN, a Radioligand with Improved Brain Kinetics
复制标题
DOI：
10.2967/jnumed.111.092338
复制
发表时间：
2012-01-01
影响因子：
9.3
通讯作者：
Horti, Andrew G.
中科院分区：
文献类型：
--
作者：
Kuwabara, Hiroto;Wong, Dean F.;Horti, Andrew G.
There are only 2 currently available radioligands, 2-F-18-FA and 6-F-18-FA, for quantitative PET of the main cerebral subtype of nicotinic acetylcholine receptors (alpha 4 beta 2-nAChRs) in humans. Both exhibit slow distribution kinetics in the brain and require several hours for PET imaging. This makes PET of nAChRs with these radioligands logistically difficult and a serious burden for human subjects. The main purpose of this study was to preclinically evaluate (2)-2-(6-F-18-fluoro-2,3'-bipyridin-5'-yl)-7-methyl7- azabicyclo[2.2.1] heptane (18F-AZAN), our new radiolabeled antagonist of alpha 4 beta 2-nAChRs, that has high binding potential and rapid brain kinetics in baboons. Methods: F-18-AZAN was synthesized using a modified F-18-FDG synthesis module. The regional distribution of F-18-AZAN in the brain was evaluated in baseline and cytisine-blocking studies of 4 male Papio anubis baboons. PET modeling procedures were used for calculation of regional distribution volume (VT), nondisplaceable binding potential (BPND), and receptor occupancy. Results: F-18-AZAN rapidly entered the baboon brain, reached a steady state within 90 min after injection, and specifically labeled cerebral nAChRs. The peak radioactivity in the thalamus was 540 (percentage standardized uptake value) at 18 6 7 min (n = 4) after bolus injection. Mathematical data analysis demonstrated that scanning for only 90 min is sufficient for determination of PET outcome variables (BPND, 3.2 [unitless] and VT, 32-35 mL/ mL in thalamus). The dose-dependent blocking experiments with cytisine demonstrated that F-18-AZAN binds specifically with beta 2-containing (predominantly alpha 4 beta 2) nAChRs. Conclusion: F-18-AZAN specifically labels nAChRs in baboon brains with a high value of BPND and it requires only 90 min of PET scanning to produce estimates of V-T and BPND in the various brain regions. The blocking of nAChRs with cytisine is dose-dependent and it showed that F-18-AZAN is suitable for application in nicotinic drug evaluation. In summary, F-18-AZAN is superior to 2-F-18-FA and 6-F-18-FA for imaging cerebral beta 2-containing nAChRs in baboons. Further evaluations of F-18-AZAN in the human brain are under way.
