Synthesis and evaluation of [¹⁸F]DOPP for PET imaging of fatty acid amide hydrolase

Objectives Fatty acid amide hydrolase (FAAH) regulates the endocannabinoid signaling and plays an important role in pain, addictions and neurological disorders. Although [¹¹C]CURB has been used in humans, ¹⁸F-labeled radiotracers with a longer half-life would present additional advantages for FAAH imaging. Biodistribution and ex vivo studies in rats using [¹⁸F]DOPP have demonstrated its high brain uptake and binding specificity to FAAH. Recent PET studies in non-human primates also showed promising results. It is therefore imperative to develop an efficient and reliable precursor synthesis. The modified precursor synthesis, radiosynthesis and in vivo imaging in rats will be discussed.

Methods The reported synthesis of the precursor intermediate oxazoline from 3-cyanophenol gave unreliable and low yields (~10%). The procedure was thus modified: esterification of 3-hydroxybenzoic acid, followed by treatment with ethanolamine and cyclization. Radiosynthesis was performed via an automated GE tracerlab FX_FN module. Dynamic microPET imaging (Siemens Inveon) in rats after injection of [¹⁸F]DOPP was carried out for 1 h. A blocking study was conducted after pretreatment with URB597 (FAAH inhibitor, 2 mg/kg, IP, 30 min prior).

Results The oxazoline was efficiently synthesized in reliable yields (>48%) via the modified procedure, leading to the FAAH precursor in an overall 21% yield. One-pot three-step radiosynthesis consistently afforded [¹⁸F]DOPP in approx. 14% yield (decay corrected) with high radiochemical purity and specific activity. PET imaging shows a high brain uptake, consistent with reported regional FAAH activity. Pretreatment with URB597 completely abolished binding in all brain regions, demonstrating the exceptional specificity of the radiotracer for FAAH (Fig.).

Conclusions To our knowledge, this is the first microPET imaging study in rats using [¹⁸F]DOPP. These results indicate that [¹⁸F]DOPP is a promising PET ligand for FAAH imaging.

Research Support NIH P41 EB017183