Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase

作者：Sadovski Oleg; Hicks Justin W; Parkes Jun; Raymond Roger; Nobrega Jose; Houle Sylvain; Cipriano Mariateresa; Fowler Christopher J; Vasdev Neil; Wilson Alan A^*

来源：Bioorganic & Medicinal Chemistry, 2013, 21(14): 4351-4357.

DOI：10.1016/j.bmc.2013.04.077

• PET
• FAAH
• Radiosynthesis
• Fluorine-18
• Rat
• Endocannabinoid
• Anandamide

Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological disorders. The synthesis, radiosynthesis, and evaluation, in vitro and ex vivo in rat, of an F-18-radiotracer designed to image FAAH using positron emission tomography (PET) is described.
Fluorine-18 labelled 3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate, [F-18]5, was synthesized at high specific activity in a one-pot three step reaction using a commercial module with a radiochemical yield of 17-22% (from [F-18]fluoride). In vitro assay using rat brain homogenates showed that 5 inhibited FAAH in a time-dependent manner, with an IC50 value of 0.82 nM after a preincubation of 60 min. Ex vivo biodistribution studies and ex vivo autoradiography in rat brain demonstrated that [F-18]5 had high brain penetration with standard uptake values of up to 4.6 and had a regional distribution which correlated with reported regional FAAH enzyme activity. Specificity of binding to FAAH with [H-18]5 was high (>90%) as demonstrated by pharmacological challenges with potent and selective FAAH inhibitors and was irreversible as demonstrated by radioactivity measurements on homogenized brain tissue extracts.
We infer from these results that [F-18]5 is a highly promising candidate radiotracer with which to image FAAH in human subjects using PET and clinical studies are proceeding.

• 出版日期2013-7-15