Toyohara Jun, Tago Tetsuro, Sakata Muneyuki
Research Team for Neuroimaging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae- cho, Itabashi-ku, Tokyo, 173-0015, Japan.
EJNMMI Radiopharm Chem. 2024 Jul 23;9(1):53. doi: 10.1186/s41181-024-00285-9.
2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) is commonly used for diagnosis of dementia because brain glucose metabolism reflects neuronal activity. However, as [F]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 [O]HO 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-[C]methylamphetamine ([C]MMP) is a possible CBF tracer with high resolution and sensitivity that exhibits comparable performance to that of [O]HO in conscious monkey brains. We performed process validation of the radiosynthesis and preclinical development of [C]MMP prior to clinical translation.
The decay-corrected yields of [C]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 [C]MMP. The acute toxicity of [C]MMP injection at 150 or 200 times, to administer a postulated dose of 740 MBq of [C]MMP, was also evaluated after the decay-out of C. No acute toxicity of MMP and [C]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.
[C]MMP shows acceptable pharmacological safety at the dose required for adequate PET imaging. The potential risk associated with [C]MMP PET imaging is well within the acceptable dose limit.
2-脱氧-2-[F]氟-D-葡萄糖（[F]FDG）常用于痴呆症的诊断，因为脑葡萄糖代谢反映神经元活动。然而，由于[F]FDG是葡萄糖的类似物，示踪剂在脑中的蓄积受血浆葡萄糖水平影响。相比之下，脑血流量（CBF）示踪剂理论上不受血浆葡萄糖水平影响，因此有望成为糖尿病患者痴呆症诊断的有用替代方法。目前用于CBF成像的技术有单光子发射计算机断层扫描（SPECT）和[O]HO正电子发射断层扫描（PET），但这些技术在区域脑成像方面的分辨率和灵敏度不足，尤其是在脑萎缩患者中。N-异丙基-4-[C]甲基苯丙胺（[C]MMP）是一种可能具有高分辨率和灵敏度的CBF示踪剂，在清醒猴脑中表现出与[O]HO相当的性能。在进行临床转化之前，我们对[C]MMP的放射性合成和临床前开发进行了工艺验证。
合成结束时[C]MMP的衰变校正产率为41.4±6.5%，放射化学纯度为99.7±0.3%，摩尔活度为192.3±22.5 MBq/nmol。所有工艺验证批次均符合产品规格。以3.55 mg/kg体重的剂量评估了MMP的急性毒性，该剂量是[C]MMP潜在最大临床剂量的10000倍。在碳衰变后，还评估了注射150或200倍剂量的[C]MMP（假定剂量为740 MBq的[C]MMP）的急性毒性。未发现MMP和[C]MMP注射有急性毒性。未观察到MMP的致突变活性。根据医学内照射剂量（MIRD）方法计算的有效剂量为5.4 µSv/MBq，膀胱壁的最大吸收剂量为57.6 µGy/MBq。MMP是一种苯烷基胺衍生物，显示与σ受体结合，但其亲和力约为现有σ受体显像剂的1/100。对其他脑内神经受体的亲和力较低。
[C]MMP在PET成像所需剂量下显示出可接受的药理安全性。与[C]MMP PET成像相关的潜在风险完全在可接受的剂量限值内。
