PURPOSE We recently introduced voxel-level images of drug occupancy from PET via our "Lassen plot filter." Occupancy images revealed clear dependence of 11C-flumazenil displacement on dose of GABAa inhibitor, CVL-865, but with different scales in different brain regions. We hypothesized that regions requiring higher drug concentrations to achieve desired occupancy would have higher EC50 values. We introduce an "EC50 image" from human data to evaluate this hypothesis. METHODS Five healthy subjects were scanned with the nonselective GABAa tracer, 11C-flumazenil, before and (twice) after administration of CVL-865. We created ten occupancy images and applied an Emax model locally to create one EC50 image. We also performed simulations to confirm our observations of regional variation in EC50 and to identify the main source of variability in EC50. RESULTS As expected, the EC50 image revealed spatial variation in apparent drug affinity. High EC50 was found in areas of low occupancy for a given drug dose. Simulations demonstrated that sampling from an inadequate range of plasma drug concentrations could impair precision. CONCLUSION Our results argue for (a) confidence in the ability of the EC50 images to identify regional differences and (b) a need to tailor the range of drug doses in an occupancy study to regularize the precision of the EC50 throughout the brain. The EC50 image could add value to early-phase drug development by identifying regional variation in affinity that might impact therapy or safety and by guiding dose selection for later-phase trials.

中文翻译：

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EC50 图像是 PET 目标占用研究的一个新终点，揭示了表观药物亲和力的空间变化。

目的 我们最近通过我们的“拉森图过滤器”从 PET 中引入了药物占用的体素级图像。占用图像显示 11C-氟马西尼置换对 GABAa 抑制剂 CVL-865 剂量的明显依赖性，但在不同脑区具有不同的尺度。我们假设需要更高药物浓度才能达到理想入住率的区域将具有更高的 EC50 值。我们从人类数据中引入“EC50 图像”来评估这一假设。方法 在给予 CVL-865 之前和之后（两次），用非选择性 GABAa 示踪剂 11C-氟马西尼对五名健康受试者进行扫描。我们创建了十张占用图像并在本地应用了一个 Emax 模型来创建一张 EC50 图像。我们还进行了模拟以确认我们对 EC50 区域变化的观察并确定 EC50 变化的主要来源。结果 正如预期的那样，EC50 图像揭示了表观药物亲和力的空间变化。对于给定的药物剂量，在占用率低的区域发现了高 EC50。模拟表明，从不适当的血浆药物浓度范围内取样可能会降低精度。结论 我们的研究结果表明 (a) 对 EC50 图像识别区域差异的能力的信心和 (b) 需要在占用研究中调整药物剂量范围以规范整个大脑的 EC50 精度。