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Abstract：
The σ1 receptors (S1Rs) are implicated in a variety of diseases including Alzheimer disease and cancer. Previous PET S1R radiotracers are characterized by slow kinetics or off-target binding that impedes their use in humans. Here, we report the first PET imaging evaluation in rhesus monkeys of 4 18F-labeled spirocyclic piperidine-based PET radiotracers (18F-1 to 18F-4). Methods: Baseline scans for the 4 radiotracers were obtained on an adult male rhesus monkey. Blocking scans were obtained with the S1R-selective agonist SA4503 to assess binding specificity of 18F-2 and 18F-4 Arterial input functions were measured, and binding parameters were determined with kinetic modeling analysis. Results: In the rhesus brain, all 4 radiotracers showed high and fast uptake. Tissue activity washout was rapid for 18F-2 and 18F-4, and much slower for 18F-1 and 18F-3, in line with their respective in vitro S1R-binding affinities. Both the 1-tissue-compartment and multilinear analysis-1 kinetic models provided good fits of time-activity curves and reliable estimates of distribution volume. Regional distribution volume values were highest in the cingulate cortex and lowest in the thalamus for all radiotracers. 18F-4 showed greater differential uptake across brain regions and 3-fold-higher binding potential than 18F-2 SA4503 at the dose of 0.5 mg/kg blocked approximately 85% (18F-2) and 95% (18F-4) of radiotracer binding. Conclusion: Tracers 18F-2 and 18F-4 displayed high brain uptake and fast tissue kinetics, with 18F-4 having higher specific binding signals than 18F-2 in the same monkey. Taken together, these data indicate that both 18F-2 and 18F-4 possess the requisite kinetic and imaging properties as viable PET tracers for imaging S1R in the human brain.
摘要：
σ1受体(S1Rs)涉及多种疾病,包括阿尔茨海默病和癌症。先前的PETS1R放射性示踪剂的特征在于缓慢的动力学或脱靶结合,这阻碍了它们在人类中的使用。这里,我们报告了4种18F标记的基于螺环哌啶的PET放射性示踪剂(18F-1至18F-4)在恒河猴中的首次PET成像评估。方法：对成年雄性恒河猴进行了4种放射性示踪剂的基线扫描。用S1R选择性激动剂SA4503获得阻断扫描以评估18F-2和18F-4的结合特异性测量动脉输入功能,并通过动力学建模分析确定了结合参数。结果：在恒河猴的大脑中，所有4个放射性示踪剂均显示出高且快速的摄取。组织活性洗脱对于18F-2和18F-4是快速的,而对于18F-1和18F-3则慢得多,与它们各自的体外S1R结合亲和力一致。1-组织区室和多线性分析-1动力学模型都提供了时间-活动曲线的良好拟合和分布体积的可靠估计。对于所有放射性示踪剂，扣带皮质的区域分布体积值最高，丘脑最低。在0.5mg/kg的剂量下,18F-4显示出跨越脑区域的更大差异摄取和比18F-2SA4503高3倍的结合潜力,阻断了大约85%(18F-2)和95%(18F-4)的放射性示踪剂结合。结论：示踪剂18F-2和18F-4显示出高的脑摄取和快速的组织动力学，其中18F-4在同一只猴子中具有比18F-2更高的特异性结合信号。一起来看,这些数据表明18F-2和18F-4都具有必要的动力学和成像特性,作为用于在人脑中成像S1R的可行PET示踪剂。
