Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Nucl Med Biol. 2013 Aug;40(6):740-6. doi: 10.1016/j.nucmedbio.2013.04.008. Epub 2013 May 31.
Fatty acid amide hydrolase (FAAH) has a significant role in regulating endocannabinoid signaling in the central nervous system. As such, FAAH inhibitors are being actively sought for pain, addiction, and other indications. This has led to the recent pursuit of positron emission tomography (PET) radiotracers targeting FAAH. We report herein the preparation and preclinical evaluation of [(11)C-carbonyl]PF-04457845, an isotopologue of the potent irreversible FAAH inhibitor.
PF-04457845 was radiolabeled at the carbonyl position via automated [(11)C]CO(2)-fixation. Ex vivo brain biodistribution of [(11)C-carbonyl]PF-04457845 was carried out in conscious rats. Specificity was determined by pre-administration of PF-04457845 or URB597 prior to [(11)C-carbonyl]PF-04457845. In a separate experiment, rats injected with the title radiotracer had whole brains excised, homogenized and extracted to examine irreversible binding to brain parenchyma.
The title compound was prepared in 5 ± 1% (n = 4) isolated radiochemical yield based on starting [(11)C]CO(2) (decay uncorrected) within 25 min from end-of-bombardment in >98% radiochemical purity and a specific activity of 73.5 ± 8.2 GBq/μmol at end-of-synthesis. Uptake of [(11)C-carbonyl]PF-04457845 into the rat brain was high (range of 1.2-4.4 SUV), heterogeneous, and in accordance with reported FAAH distribution. Saturable binding was demonstrated by a dose-dependent reduction in brain radioactivity uptake following pre-treatment with PF-04457845. Pre-treatment with the prototypical FAAH inhibitor, URB597, reduced the brain radiotracer uptake in all regions by 71-81%, demonstrating specificity for FAAH. The binding of [(11)C-carbonyl]PF-04457845 to FAAH at 40 min post injection was irreversible as 98% of the radioactivity in the brain could not be extracted.
[(11)C-carbonyl]PF-04457845 was rapidly synthesized via an automated radiosynthesis. Ex vivo biodistribution studies in conscious rodents demonstrate that [11C PF-04457845 is a promising candidate radiotracer for imaging FAAH in the brain with PET. These results coupled with the known pharmacology and toxicology of PF-04457845 should facilitate clinical translation of this radiotracer.
脂肪酸酰胺水解酶（FAAH）在中枢神经系统内的内源性大麻素信号转导中具有重要作用。因此，FAAH 抑制剂正被积极地用于治疗疼痛、成瘾和其他疾病。这导致了最近对靶向 FAAH 的正电子发射断层扫描（PET）放射性示踪剂的追求。我们在此报告了通过自动化[(11)C]CO2-固定在羰基位置标记的[(11)C-羰基]PF-04457845 的制备和临床前评估，PF-04457845 是一种强效不可逆 FAAH 抑制剂的同位素类似物。
通过自动化[(11)C]CO2-固定在羰基位置对 PF-04457845 进行放射性标记。在清醒大鼠中进行[(11)C-羰基]PF-04457845 的脑外分布研究。通过在[(11)C-羰基]PF-04457845 之前预先给予 PF-04457845 或 URB597 来确定特异性。在另一个实验中，用标题放射性示踪剂注射的大鼠切除整个大脑，匀浆并提取，以检查对脑实质的不可逆结合。
标题化合物是在 25 分钟内从末端轰击结束时以 5±1%（n=4）的放射性化学产率制备的，基于起始的[(11)C]CO2（未校正衰变），放射性化学纯度大于 98%，合成结束时的比活度为 73.5±8.2GBq/μmol。[(11)C-羰基]PF-04457845 在大鼠脑中的摄取量很高（范围为 1.2-4.4 SUV），不均匀，与报道的 FAAH 分布一致。通过预给药 PF-04457845，脑放射性摄取的剂量依赖性降低，证明了饱和结合。用原型 FAAH 抑制剂 URB597 预处理，所有区域的脑放射性示踪剂摄取减少 71-81%，证明了对 FAAH 的特异性。在注射后 40 分钟，[(11)C-羰基]PF-04457845 与 FAAH 的结合是不可逆的，因为大脑中的 98%放射性不能被提取。
[(11)C-羰基]PF-04457845 通过自动化放射性合成快速合成。在清醒啮齿动物中的离体生物分布研究表明，[11C-PF-04457845 是一种很有前途的候选放射性示踪剂，可用于通过 PET 成像大脑中的 FAAH。这些结果加上 PF-04457845 的已知药理学和毒理学特性，应该有助于该放射性示踪剂的临床转化。
