Nicotinic α4β2 receptor imaging agents -: Part II.: Synthesis and biological evaluation of 2-[18F]fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (18F-nifene) in rodents and imaging by PET in nonhuman primate
Nicotinic α4β2 receptor imaging agents -: Part II.: Synthesis and biological evaluation of 2-[18F]fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (18F-nifene) in rodents and imaging by PET in nonhuman primate
复制标题
DOI：
10.1016/j.nucmedbio.2005.12.017
复制
发表时间：
2006-04-01
影响因子：
3.1
通讯作者：
Mukherjee, J
中科院分区：
文献类型：
--
作者：
Pichika, R;Easwaramoorthy, B;Mukherjee, J
α 4 β 2烟碱乙酰胆碱受体（nAChR）与多种神经退行性疾病有关。因此，这种受体非常需要最佳的正电子发射断层扫描（PET）显像剂。本文报道了2-氟-3-[2-（(S)-3-吡咯啉基）甲氧基]吡啶（尼芬）的发展和初步评价。h -3-胞氨酸对尼芬在大鼠脑匀浆中α 4 β 2位点的结合K-i=0.50 nM。2- f -18-氟-3-[2-(S)-3-吡咯啉基)甲氧基]吡啶（f -18-硝基）的放射合成在2.5 h内完成，经衰变校正后，总放射化学产率为40-50%。具体活度估计约为。37-185 GBq/mu mol。大鼠脑片体外全放射成像显示，f -18-尼芬选择性结合于丘脑腹侧核（AVT）、丘脑、丘下、纹状体、皮质等与α 4 β 2受体分布一致的区域。大鼠小脑有一定的结合，而海马区域的结合最低。f18 -nifene在大鼠脑切片中测定了AVT与小脑之间>13的最高比值。300 μ M尼古丁使这些脑区特异性结合降低（> 95%）。采用全ECAT EXACT HR+扫描仪对麻醉恒河猴F-18-nifene （130 MBq）进行正电子发射断层成像研究。PET研究显示，在丘脑前内侧、腹外侧、外侧膝状回、扣带回、颞叶皮层（包括耻骨下）区域选择性摄取最大。与其他区域相比，猴子小脑的结合程度较低，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。f -18-尼芬更快的结合谱表明其作为PET显像剂的前景，因此需要进一步的评估。(c) 2006爱思唯尔公司版权所有。
The alpha 4 beta 2 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-fluro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (nifene). In vitro binding affinity of nifene in rat brain homogenate using H-3-cytisine exhibited a K-i=0.50 nM for the alpha 4 beta 2 sites. The radiosynthesis of 2-F-18-fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine (F-18-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/mu mol. In vitro alltoradiography in rat brain slices indicated selective binding of F-18-nifene to anteroventral thalamic (AVT) nucleus, thalamus, subiculum, striata, cortex and other regions consistent with alpha 4 beta 2 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 F-18-nifene in rat brain slices. The specific binding was reduced (> 95%) by 300 mu M nicotine in these brain regions. Positron emission tomography imaging Study of F-18-nifene (130 MBq) in anesthetized rhesus monkey was carried Out using all 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 F-18-nifene indicates promise as a PET imaging agent and thus needs further evaluation. (c) 2006 Elsevier Inc. All rights reserved.