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Time course of dopamine transporter (DAT) occupancy of a long-acting formulation of dexmethylphenidate

¹ Nuclear Medicine; ² Psychiatry, MGH, Boston, Massachusetts; ³ Chemistry, Organix, Woburn, Massachusetts

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Objectives: Preclinical studies suggest interference from the l-enantiomer of MPH. The relationship of plasma d-MPH levels to DAT occupancy has been documented for d,l-MPH but not d-MPH.

Methods: 18 healthy volunteers underwent PET imaging after administration of oral doses of a long-acting formulation of d-MPH (d-MPH ER). Doses of 20, 30, and 40 mgs were tested at 1,8,10,12 & 14 (40 mgs only) h. Subjects were injected with ~5 mCi of ¹¹C Altropane and serial images of the brain were acquired with a Siemens HR+ PET camera. Binding potential (BP,k₃/k₄) was calculated from TACs using the simplified reference region method with cerebellum as reference.

Results: The highest CNS DAT occupancies were at 1 and 8 h, there was a gradual decrease at 10, 12 and 14 h (40 mg). At 20 mg, the highest occupancies were about 50%, the lowest 27% (12 h). At 40 mg, the highest occupancies were over 60%, the lowest 39.9% (14 h). A plasma concentration of 8.3 ng/ml of d-MPH was associated with a 50% blockade of DAT for oral d-MPH ER. The comparable plasma concentration from other studies of racemic MPH, was 6.3 ng/ml.

Conclusions: DAT Occupancies were found to be internally consistent by dose and hour. However , they were lower than those reported for the same plasma levels in studies of oral racemic MPH. Oral isomeric d-MPH has previously been shown to be clinically effective at these same doses and plasma levels. These findings suggest that there is a specific DAT occupancy, associated with clinical effectiveness, that is lower than that previously measured. The findings also suggest that oral l-MPH produces a non specific blocking that contributes to the apparent higher DAT occupancies recorded previously with racemic MPH.

Research Support: Novartis

This Article Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Fischman, A. Articles by Meltzer, P. PubMed Articles by Fischman, A. Articles by Meltzer, P.