18F-FMPEP-d2

Obesity is a pressing public health concern worldwide. Novel pharmacological means are urgently needed to combat the increase of obesity and accompanying type 2 diabetes (T2D). Although fully established obesity is associated with neuromolecular alterations and insulin resistance in the brain, potential obesity-promoting mechanisms in the central nervous system have remained elusive. In this triple-tracer positron emission tomography study, we investigated whether brain insulin signaling, μ-opioid receptors (MORs) and cannabinoid CB1 receptors (CB1Rs) are associated with risk for developing obesity.

Subjects were 41 young non-obese males with variable obesity risk profiles. Obesity risk was assessed by subjects’ physical exercise habits, body mass index and familial risk factors, including parental obesity and T2D. Brain glucose uptake was quantified with [18F]FDG during hyperinsulinemic euglycemic clamp, MORs were quantified with [11C]carfentanil and CB1Rs with [18F]FMPEP-d2.

Subjects with higher obesity risk had globally increased insulin-stimulated brain glucose uptake (19 high-risk subjects versus 19 low-risk subjects), and familial obesity risk factors were associated with increased brain glucose uptake (38 subjects) but decreased availability of MORs (41 subjects) and CB1Rs (36 subjects).

These results suggest that the hereditary mechanisms promoting obesity may be partly mediated via insulin, opioid and endocannabinoid messaging systems in the brain.

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.