Synthesis And ～(125)Ⅰ Labeling Of A Precursor For Imaging Nicotinic Acetylcholine Receptors

Nicotinic acetylcholine receptors (nAChRs), which usually exist in brain, spinal cord and other nervous tissue, are close related to the various pharmacological effects or disease states, such as seizure, analgesia, Parkinson' Disease (PD), Alzheimer's Disease (AD) and tobacco addiction. Also, nAChRs is one of the target molecules to treat epilepsy syndrome and hyperalgia. It will be very appealing to image nAChRs in vivo, diagnosis or treat the disease above, and probe the mechanism of nAChRs in tobacco addiction if the suitable radionuclides labeled compound can be synthesized. However, no report was involved in the labeled compounds for imaging nAChRs in China until now.[11C]](-)-Nicotine was the first ligand for imaging nAChRs. Unfortunately, it was not suitable in clinical use because of the high nonspecific binding and speed clearance from brain. Fortunately, A-85380, a series of analogs with nicotine structure, have been regarded as the most promising compounds for imaging nAChRs more recently, due to their high specific affinity and less toxicity. In other hand, compared with 18F (T1/2=110min), 123I(T1/2=13.2h) labeled ligands can provide more imaging time by more available SPECT, and there exist at least two radioisotopes with longer half life, such as 125I(T1/2=65d) or 131I(T1/2=8.3d), which can be used to the substitute of 123I for exploring the experimental conditions or animal study in vitro and in vivo.For these reason, in this paper, (s)-5-(tri-butylstannyl)-3{[1-(tert-butoxycarbonyl)-2-azetidinyl]methoxy}pyridine, a precursor for imagingnAChRs was synthesized in several steps and with modified procedure, and was further labeled with 125/23I. Firstly, 3-hydroxy-5-bromopyridine was synthesized by 2-furfurylamine reacting with hydrobromic acid, while(s)-1(tert-Butoxycarbonyl)-2-azetidinemethanol was synthesized using (s)-2-azetidinecarboxylic as starting material. Then,(s)-5-bromo-3-[[1(tert-Butoxycarbonyl)-2-azetidinyl]methoxy] pyridine was synthesized by reaction of the two products above. Finally, (s)-5-(tri-butylstannyl)-3{[1-(tert-butoxycarbonyl)-2-azetidinyl]methoxy}pyridine was obtained by the reaction of (s)-5-bromo-3-[[1(tert-Butoxycarbonyl)-2-azetidinyl]methoxy] pyridine and bis(tributyltin) under the catalysis of tetrakis(trophenylphosphine)palladium. The synthesis procedures, experimental conditions and purification procedures for the compounds were investigated, respectively. Moreover, all the intermediate and product compounds were characterized or analyzed by NMR, MS or HPLC.The resulted (s)-5-(tri-butylstannyl)- 3{[1-(tert-butoxycarbonyl) -2-azetidinyl]methoxy}pyridine was labeled with 125I in labeling yield of more than 30% with radiochemical purity of more than 98%. Even stayed for 3 days at room temperature (RT), the purified 5-[125I]-I-85380 maintained constantly stable in vitro, with radiochemical purity of more than 95%.In summary, a precursor for imaging nAChRs was synthesized by the modified procedure and labeled with 125I. The results will be very important to further synthesis of [123I]5-I-A-85380 and imaging study of nAChRs in vivo.