18F-FMPEP-d2

Here, we describe the development of an in‐house‐built device for the fully automated multistep synthesis of the cannabinoid CB1 receptor imaging tracer (3R,5R)‐5‐(3‐([18F]fluoromethoxy‐d2)phenyl)‐3‐(((R)‐1‐phenylethyl)amino)‐1‐(4‐(trifluoromethyl)phenyl)pyrrolidin‐2‐one ([18F]FMPEP‐d2), following good manufacturing practices. The device is interfaced to a HPLC and a sterile filtration unit in a clean room hot cell. The synthesis involves the nucleophilic 18F‐fluorination of an alkylating agent and its GC purification, the subsequent 18F‐fluoroalkylation of a precursor molecule, the semipreparative HPLC purification of the 18F‐fluoroalkylated product, and its formulation for injection. We have optimized the duration and temperature of the 18F‐fluoroalkylation reaction and addressed the radiochemical stability of the formulated product. During the past 5 years (2013–2018), we have performed a total of 149 syntheses for clinical use with a 90% success rate. The activity yield of the formulated product has been 1.0 ± 0.4 GBq starting from 11 ± 2 GBq and the molar activity 600 ± 300 GBq/μmol at the end of synthesis.

Sections of rat BAT and subcutaneous white adipose tissue (WAT) were stained for CB1 and uncoupling protein-1 by immunofluorescent staining. Binding of the radiolabeled CB1 antagonist (3R,5R)-5-(3-(18F-fluoromethoxy)phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)-phenyl)pyrrolidin-2-one ((18)F-FMPEP-d2) to BAT in vivo and in vitro was assessed in rats by PET.

We found that CB1 was colocalized with uncoupling protein-1 in BAT, but neither protein was found in WAT. Binding of the radiotracer to BAT sections (but not WAT) in vitro was high and displaceable by pretreatment with rimonabant. Deposits of BAT in rats had significant binding of (18)F-FMPEP-d2 in vivo, indicating high CB1 density. WAT deposits were negative for (18)F-FMPEP-d2, consistent with the immunofluorescent staining and in vitro results.

(18)F-FMPEP-d2 PET can quantify CB1 density noninvasively in vivo in rats. CB1 is therefore a promising surrogate imaging biomarker for assessing the presence of BAT deposits as well as for elucidating the mechanism of CB1 antagonist-mediated weight loss.