Abstract
ObjectiveThe α7 nicotinic acetylcholine receptors (nAChRs) play a vital role in the pathophysiology of neuropsychiatric diseases such as Alzheimer’s disease and depression. However, there is currently no suitable positron emission tomography (PET) or Single-Photon Emission Computed Tomography (SPECT) radioligands for imaging α7 nAChRs in brain. Here our aim is to radiosynthesize a novel SPECT radioligand 131I-CHIBA-1001 for whole body biodistribution study and in vivo imaging of α7 nAChRs in brain.Method 131I-CHIBA-1001 was radiosynthesized by chloramine-T method. Different conditions of reaction time and temperature were tested to get a better radiolabeling yield. Radiolabeling yield and radiochemical purities of 131I-CHIBA-1001 were analyzed by thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) system. Whole body biodistribution study was performed at different time points post injection of 131I-CHIBA-1001 in KM mice. Monkey subject was used for in vivo SPECT imaging in brain.ResultThe radiolabeling yield of 131I-CHIBA-1001 reached 96% within 1.5∼2.0 h at 90∼95°C. The radiochemical purity reached more than 99% after HPLC purification. 131I-CHIBA-1001 was highly stable in saline and fresh human serum in room temperature and 37°C separately. The biodistribution data of brain at 15, 30, and 60 min were 11.05±1.04%ID/g, 8.8±0.04%ID/g and 6.28±1.13%ID/g, respectively. In experimental SPECT imaging, the distribution of radioactivity in the brain regions was paralleled with the distribution of α7 nAChRs in the monkey brain. Moreover, in the blocking SPECT imaging study, the selective α7 nAChR agonist SSR180711 blocked the radioactive uptake in the brain successfully.ConclusionThe CHIBA-1001 can be successfully radiolabeled with 131I using the chloramine-T method. 131I-CHIBA-1001 can successfully accumulate in the monkey brain and image the α7 acetylcholine receptors. 131I-CHIBA-1001 can be a candidate for imagingα7 acetylcholine receptors, which will be of great value for the diagnosis and treatment of mental diseases.
Highlights
Neuronal nicotinic acetylcholine receptors, which are members of the four transmembrane domain superfamily of neurotransmitter-gated ion channels, are pentameric combinations of a and a/b subunits, with a high degree of complexity conferred by 12 different a (a2–a10) and b (b2–b4) subunits [1]
The CHIBA-1001 can be successfully radiolabeled with 131I using the chloramine-T method. 131I-CHIBA-1001 can successfully accumulate in the monkey brain and image the a7 acetylcholine receptors. 131I-CHIBA-1001 can be a candidate for imaginga7 acetylcholine receptors, which will be of great value for the diagnosis and treatment of mental diseases
A7 nicotinic acetylcholine receptors (a7 nAChRs) are currently being investigated as a potential therapeutic target for cognitive disturbances in schizophrenia and Alzheimer disease based on data from small open clinical studies [4]
Summary
Neuronal nicotinic acetylcholine receptors (nAChRs), which are members of the four transmembrane domain superfamily of neurotransmitter-gated ion channels, are pentameric combinations of a and a/b subunits, with a high degree of complexity conferred by 12 different a (a2–a10) and b (b2–b4) subunits [1]. Neuronal nAChRs play an array of critical roles in the central nervous system (CNS), only in the last two decades a rapid growing understanding of subtype localization has been associated with potential therapeutic applications. A7 nicotinic acetylcholine receptors (a7 nAChRs) are currently being investigated as a potential therapeutic target for cognitive disturbances in schizophrenia and Alzheimer disease based on data from small open clinical studies [4].
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