[(18)F]FMeNER-D2: A systematic in vitro analysis of radio-metabolism

The norepinephrine transporter (NET) presents an important target for therapy and diagnosis of ADHD and other neurodegenerative and psychiatric diseases. Thus, PET is the diagnostic method of choice, using radiolabeled NET-ligands derived from reboxetine. So far, [(18)F]FMeNER-D2 showed best pharmacokinetic and -dynamic properties. However, the disadvantage of reboxetine derived PET tracers is their high metabolic cleavage-resulting in impeding signals in the PET scans, which hamper a proper quantification of the NET in cortical areas.

Metabolic stability testing was performed in vitro using a plethora of human and murine enzymes.

No metabolism was observed using monoamine oxidase A and B or catechol-O-methyl transferase. Incubation of [(18)F]FMeNER-D2 with CYP450-enzymes, predominantly located in the liver, led to a significant and fast metabolism of the tracer. Moreover, the arising three radiometabolites were found to be more polar than [(18)F]FMeNER-D2. Surprisingly, definitely no formation of free [(18)F]fluoride was observed.

According to our in vitro data, the interfering uptake in cortical regions might be attributed to these emerging radiometabolites but does not reflect bonding in bone due to defluorination. Further research on these radiometabolites is necessary to elucidate the in vivo situation. This might include an analysis of human blood samples after injection of [(18)F]FMeNER-D2, to enable a better correction of the PET-input function.