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

INTRODUCTION: 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. METHODS: Metabolic stability testing was performed in vitro using a plethora of human and murine enzymes. RESULTS: 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. CONCLUSION: 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.

The norepinephrine transporter in attention-deficit/hyperactivity disorder investigated with positron emission tomography.

IMPORTANCE: Attention-deficit/hyperactivity disorder (ADHD) research has long focused on the dopaminergic system's contribution to pathogenesis, although the results have been inconclusive. However, a case has been made for the involvement of the noradrenergic system, which modulates cognitive processes, such as arousal, working memory, and response inhibition, all of which are typically affected in ADHD. Furthermore, the norepinephrine transporter (NET) is an important target for frequently prescribed medication in ADHD. Therefore, the NET is suggested to play a critical role in ADHD. OBJECTIVE: To explore the differences in NET nondisplaceable binding potential (NET BPND) using positron emission tomography and the highly selective radioligand (S,S)-[18F]FMeNER-D2 [(S,S)-2-(α-(2-[18F]fluoro[2H2]methoxyphenoxy)benzyl)morpholine] between adults with ADHD and healthy volunteers serving as controls. DESIGN, SETTING, AND PARTICIPANTS: Twenty-two medication-free patients with ADHD (mean [SD] age, 30.7 [10.4] years; 15 [68%] men) without psychiatric comorbidities and 22 age- and sex-matched healthy controls (30.9 [10.6] years; 15 [68%] men) underwent positron emission tomography once. A linear mixed model was used to compare NET BPND between groups. MAIN OUTCOMES AND MEASURES: The NET BPND in selected regions of interest relevant for ADHD, including the hippocampus, putamen, pallidum, thalamus, midbrain with pons (comprising a region of interest that includes the locus coeruleus), and cerebellum. In addition, the NET BPND was evaluated in thalamic subnuclei (13 atlas-based regions of interest). RESULTS: We found no significant differences in NET availability or regional distribution between patients with ADHD and healthy controls in all investigated brain regions (F1,41<0.01; P=.96). Furthermore, we identified no significant association between ADHD symptom severity and regional NET availability. Neither sex nor smoking status influenced NET availability. We determined a significant negative correlation between age and NET availability in the thalamus (R2=0.29; P<.01 corrected) and midbrain with pons, including the locus coeruleus (R2=0.18; P<.01 corrected), which corroborates prior findings of a decrease in NET availability with aging in the human brain. CONCLUSIONS AND RELEVANCE: Our results do not indicate involvement of changes in brain NET availability or distribution in the pathogenesis of ADHD. However, the noradrenergic transmitter system may be affected on a different level, such as in cortical regions, which cannot be reliably quantified with this positron emission tomography ligand. Alternatively, different key proteins of noradrenergic neurotransmission might be affected.