Pichika Rama, Easwaramoorthy Balasubramaniam, Collins Daphne, Christian Bradley T, Shi Bingzhi, Narayanan Tanjore K, Potkin Steven G, Mukherjee Jogeshwar
Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-3960, USA.
Nucl Med Biol. 2006 Apr;33(3):295-304. doi: 10.1016/j.nucmedbio.2005.12.017.
The alpha4beta2 nicotinic acetylcholine receptor (nAChR) has been implicated in various neurodegenerative diseases. Optimal positron emission tomography (PET) imaging agents are therefore highly desired for this receptor. We report here the development and initial evaluation of 2-fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (nifene). In vitro binding affinity of nifene in rat brain homogenate using 3H-cytisine exhibited a K(i) = 0.50 nM for the alpha4beta2 sites. The radiosynthesis of 2-18F-fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (18F-nifene) was accomplished in 2.5 h with an overall radiochemical yield of 40-50%, decay corrected. The specific activity was estimated to be approx. 37-185 GBq/micromol. In vitro autoradiography in rat brain slices indicated selective binding of 18F-nifene to anteroventral thalamic (AVT) nucleus, thalamus, subiculum, striata, cortex and other regions consistent with alpha4beta2 receptor distribution. Rat cerebellum showed some binding, whereas regions in the hippocampus had the lowest binding. The highest ratio of >13 between AVT and cerebellum was measured for 18F-nifene in rat brain slices. The specific binding was reduced (>95%) by 300 microM nicotine in these brain regions. Positron emission tomography imaging study of 18F-nifene (130 MBq) in anesthetized rhesus monkey was carried out using an ECAT EXACT HR+ scanner. PET study showed selective maximal uptake in the regions of the anterior medial thalamus, ventro-lateral thalamus, lateral geniculate, cingulate gyrus, temporal cortex including the subiculum. The cerebellum in the monkeys showed lower binding than the other regions. Thalamus-to-cerebellum ratio peaked at 30-35 min postinjection to a value of 2.2 and subsequently reduced. The faster binding profile of 18F-nifene indicates promise as a PET imaging agent and thus needs further evaluation.
α4β2烟碱型乙酰胆碱受体（nAChR）与多种神经退行性疾病有关。因此，对于该受体而言，非常需要理想的正电子发射断层扫描（PET）成像剂。我们在此报告2-氟-3-[2-((S)-3-吡咯啉基)甲氧基]吡啶（尼非尼）的研发及初步评估。使用3H-金雀花碱测定尼非尼在大鼠脑匀浆中的体外结合亲和力，其对α4β2位点的K(i) = 0.50 nM。2-18F-氟-3-[2-((S)-3-吡咯啉基)甲氧基]吡啶（18F-尼非尼）的放射性合成在2.5小时内完成，经衰变校正后的总放射化学产率为40 - 50%。比活度估计约为37 - 185 GBq/μmol。大鼠脑切片的体外放射自显影表明，18F-尼非尼与前腹侧丘脑（AVT）核、丘脑、海马下托、纹状体、皮质及其他与α4β2受体分布一致的区域有选择性结合。大鼠小脑有一些结合，而海马区的结合最低。在大鼠脑切片中，AVT与小脑之间的最高比值大于13，是针对18F-尼非尼测定的。在这些脑区中，300 μM尼古丁可使特异性结合降低（>95%）。使用ECAT EXACT HR+扫描仪对麻醉的恒河猴进行了18F-尼非尼（130 MBq）的正电子发射断层扫描成像研究。PET研究显示，在前内侧丘脑、腹外侧丘脑、外侧膝状体、扣带回、包括海马下托的颞叶皮质区域有选择性的最大摄取。猴子的小脑显示出比其他区域更低的结合。丘脑与小脑的比值在注射后30 - 35分钟达到峰值，为2.2，随后下降。18F-尼非尼更快的结合特征表明其有望成为一种PET成像剂，因此需要进一步评估。
