Evaluation of radioiodinated 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine as a ligand for SPECT investigations of brain nicotinic acetylcholine receptors.
5-Iodo-3-(2(S)-azetidinylmethoxy)pyridine (5IA), an A-85380 analog iodinated at the 5-position of the pyridine ring, was evaluated as a radiopharmaceutical for investigating brain nicotinic acethylcholine receptors (nAChRs) by single photon emission computed tomography (SPECT). [123/125I]5IA was synthesized by the iododestannylation reaction under no-carrier-added conditions and purified by high-performance liquid chromatography (HPLC) with high radiochemical yield (50%), high radiochemical purity (> 98%), and high specific radioactivity (> 55 GBq/micromol). The binding affinity of 5IA for brain nAChRs was measured in terms of displacement of [3H]cytisine and [125I]5IA from binding sites in rat cortical membranes. The binding data revealed that the affinity of 5IA was the same as that of A-85380 and more than seven fold higher than that of (-)-nicotine, and that 5IA bound selectively to the alpha4beta2 nAChR subtype. Biodistribution studies in rats indicated that the brain uptake of [125I]51A was rapid and profound. Regional cerebral distribution studies in rats demonstrated that the accumulation of [125I]5IA was consistent with the density of high affinity nAChRs with highest uptake observed in the nAChR-rich thalamus, moderate uptake in the cortex and lowest uptake in the cerebellum. Administration of the nAChR agonists (-)-cytisine and (-)-nicotine reduced the uptake of [125I]5IA in all regions studied with most pronounced reduction in the thalamus, and resulted in similar levels of radioactivity throughout the brain. [125I]5IA binding sites were shown to be saturable with unlabeled 5IA. Behavioral studies in mice demonstrated that 5IA did not show signs of behavioral toxicity. Furthermore, SPECT studies with [123I]5IA in the common marmoset demonstrated appropriate brain uptake and regional localization for a high-affinity nAChR imaging radiopharmaceutical. These results suggested that [123I]5IA is a promising radiopharmaceutical for SPECT studies of central nAChRs in human subjects.
Graduate School of Pharmaceutical Sciences, Kyoto University, Japan. hsaji@pharm.kyoto-u.ac.jp
Hideo
H
Saji
Mikako
M
Ogawa
Masashi
M
Ueda
Yasuhiko
Y
Iida
Yasuhiro
Y
Magata
Akiko
A
Tominaga
Hidekazu
H
Kawashima
Youji
Y
Kitamura
Masaki
M
Nakagawa
Yasushi
Y
Kiyono
Takahiro
T
Mukai
D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000633:toxicity; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002144:Callithrix; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000633:toxicity; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D011913:Rats, Inbred BB; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014915:Whole-Body Counting
C426745:5-iodo-3-(2-azetidinylmethoxy)pyridine; D001384:Azetidines; D011725:Pyridines; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic