Duration and degree of norepinephrine transporter occupancy by oral methylphenidate with (S,S)-[11C]MRB in healthy subjects

Objectives The neurochemical mechanisms of ADHD are poorly understood. Methylphenidate (MP), the most common treatment for ADHD, blocks dopamine transporters. MP binds to the norepinephrine transporter (NET) and inhibits NE uptake more than DA uptake (IC₅₀ 38 vs. 193 nM). This is the first PET study using the NET ligand (S,S)-[¹¹C]methylreboxetine (MRB) to determine the duration and degree of NET occupancy by MP.

Methods Subjects received placebo and MP (40 mg) 75, 150, and 225 min before each scan. For the occupancy study subjects received placebo and MP 2.5 mg, 10 mg, and 40 mg 75 min before each scan. After injection of ¹¹C-MRB (20 mCi), 2 h dynamic PET acquisition with HRRT was performed. Parametric images were computed using the multilinear reference tissue model (MRTM2) with occipital cortex as the reference region. Regions from the AAL template and regions such as locus coeruleus, raphe, hypothalamus and thalamus were analyzed. BP_ND (non-displaceable binding potential) and IC₅₀ values were estimated.

Results 1. There was no significant difference in BP_ND values after 75 min compared to 150 or 225 min.2. BP_ND was reduced by MP in a dose-dependent manner in all NET-rich regions.3. The mean IC₅₀ was 9 mg (range 2-19 mg).4. At 40 mg, MP completely displaced MRB in LC, raphe and hypothalamus, but only 50-70% in thalamus.

Conclusions Oral MP reached peak NET occupancy by 75 min (duration at least 3 hrs) occupying NET in a dose-dependent manner. MP significantly occupies NET at clinically relevant doses suggesting an important role for NET in ADHD.