PDF(Pubmed)
Abstract：
BACKGROUND: 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is commonly used for diagnosis of dementia because brain glucose metabolism reflects neuronal activity. However, as [18F]FDG is an analogue of glucose, accumulation of tracer in the brain is affected by plasma glucose levels. In contrast, cerebral blood flow (CBF) tracers are theoretically unaffected by plasma glucose levels and are therefore expected to be useful alternatives for the diagnosis of dementia in patients with diabetes. The techniques currently used for CBF imaging using single photon emission computed tomography (SPECT) and [15O]H2O positron emission tomography (PET), but these are limited by their insufficient resolution and sensitivity for regional brain imaging, especially in patients with brain atrophy. N-isopropyl-4-[11C]methylamphetamine ([11C]MMP) is a possible CBF tracer with high resolution and sensitivity that exhibits comparable performance to that of [15O]H2O in conscious monkey brains. We performed process validation of the radiosynthesis and preclinical development of [11C]MMP prior to clinical translation.
RESULTS: The decay-corrected yields of [11C]MMP at the end of synthesis were 41.4 ± 6.5%, with 99.7 ± 0.3% radiochemical purity, and 192.3 ± 22.5 MBq/nmol molar activity. All process validation batches complied with the product specifications. The acute toxicity of MMP was evaluated at a dose of 3.55 mg/kg body weight, which is 10,000 times the potential maximum clinical dose of [11C]MMP. The acute toxicity of [11C]MMP injection at 150 or 200 times, to administer a postulated dose of 740 MBq of [11C]MMP, was also evaluated after the decay-out of 11C. No acute toxicity of MMP and [11C]MMP injection was found. No mutagenic activity was observed for MMP. The effective dose calculated according to the Medical Internal Radiation Dose (MIRD) method was 5.4 µSv/MBq, and the maximum absorbed dose to the bladder wall was 57.6 µGy/MBq. MMP, a derivative of phenylalkylamine, showed binding to the sigma receptor, but had approximately 1/100 of the affinity of existing sigma receptor imaging agents. The affinity for other brain neuroreceptors was low.
CONCLUSIONS: [11C]MMP shows acceptable pharmacological safety at the dose required for adequate PET imaging. The potential risk associated with [11C]MMP PET imaging is well within the acceptable dose limit.
RESULTS: The decay-corrected yields of [11C]MMP at the end of synthesis were 41.4 ± 6.5%, with 99.7 ± 0.3% radiochemical purity, and 192.3 ± 22.5 MBq/nmol molar activity. All process validation batches complied with the product specifications. The acute toxicity of MMP was evaluated at a dose of 3.55 mg/kg body weight, which is 10,000 times the potential maximum clinical dose of [11C]MMP. The acute toxicity of [11C]MMP injection at 150 or 200 times, to administer a postulated dose of 740 MBq of [11C]MMP, was also evaluated after the decay-out of 11C. No acute toxicity of MMP and [11C]MMP injection was found. No mutagenic activity was observed for MMP. The effective dose calculated according to the Medical Internal Radiation Dose (MIRD) method was 5.4 µSv/MBq, and the maximum absorbed dose to the bladder wall was 57.6 µGy/MBq. MMP, a derivative of phenylalkylamine, showed binding to the sigma receptor, but had approximately 1/100 of the affinity of existing sigma receptor imaging agents. The affinity for other brain neuroreceptors was low.
CONCLUSIONS: [11C]MMP shows acceptable pharmacological safety at the dose required for adequate PET imaging. The potential risk associated with [11C]MMP PET imaging is well within the acceptable dose limit.
摘要：
背景:2-脱氧-2-[18F]氟-D-葡萄糖([18F]FDG)通常用于痴呆的诊断,因为脑葡萄糖代谢反映神经元活性。然而,因为[18F]FDG是葡萄糖的类似物，脑中示踪剂的积累受血浆葡萄糖水平的影响。相比之下,脑血流量(CBF)示踪剂理论上不受血糖水平的影响,因此有望成为糖尿病患者痴呆诊断的有用替代方法.目前使用单光子发射计算机断层扫描（SPECT）和[15O]H2O正电子发射断层扫描（PET）进行CBF成像的技术，但是由于它们对局部脑成像的分辨率和灵敏度不足，尤其是脑萎缩患者.N-异丙基-4-[11C]甲基苯丙胺（[11C]MMP）是一种可能的CBF示踪剂，具有高分辨率和灵敏度，在有意识的猴子大脑中表现出与[15O]H2O相当的性能。在临床翻译之前，我们对[11C]MMP的放射合成和临床前发展进行了过程验证。
结果：合成结束时[11C]MMP的衰减校正产率为41.4±6.5％，放射化学纯度为99.7±0.3%，和192.3±22.5MBq/nmol摩尔活性。所有工艺验证批次均符合产品规格。以3.55mg/kg体重的剂量评估MMP的急性毒性，这是[11C]MMP潜在最大临床剂量的10,000倍。[11C]MMP注射液的急性毒性为150或200倍，为了给药740MBq的[11C]MMP，在11C衰减后也进行了评估。未发现MMP和[11C]MMP注射液的急性毒性。未观察到MMP的诱变活性。根据医学内部辐射剂量（MIRD）方法计算的有效剂量为5.4µSv/MBq，膀胱壁的最大吸收剂量为57.6µGy/MBq。MMP,苯烷基胺的衍生物，显示与σ受体结合，但具有现有σ受体显像剂的约1/100的亲和力。对其他脑神经受体的亲和力较低。
结论：[11C]MMP在充分PET成像所需的剂量下显示出可接受的药理学安全性。与[11C]MMPPET成像相关的潜在风险在可接受的剂量范围内。
结果：合成结束时[11C]MMP的衰减校正产率为41.4±6.5％，放射化学纯度为99.7±0.3%，和192.3±22.5MBq/nmol摩尔活性。所有工艺验证批次均符合产品规格。以3.55mg/kg体重的剂量评估MMP的急性毒性，这是[11C]MMP潜在最大临床剂量的10,000倍。[11C]MMP注射液的急性毒性为150或200倍，为了给药740MBq的[11C]MMP，在11C衰减后也进行了评估。未发现MMP和[11C]MMP注射液的急性毒性。未观察到MMP的诱变活性。根据医学内部辐射剂量（MIRD）方法计算的有效剂量为5.4µSv/MBq，膀胱壁的最大吸收剂量为57.6µGy/MBq。MMP,苯烷基胺的衍生物，显示与σ受体结合，但具有现有σ受体显像剂的约1/100的亲和力。对其他脑神经受体的亲和力较低。
结论：[11C]MMP在充分PET成像所需的剂量下显示出可接受的药理学安全性。与[11C]MMPPET成像相关的潜在风险在可接受的剂量范围内。
