Occupancy of dopamine transporter and the effect of dopamine reuptake inhibition by mazindol in living human brain

Objectives Regional alterations in extracellular dopamine levels can be observed in the striatum during performance of neuropsychological tasks using PET. To increase detection of the alteration, dopamine reuptake inhibitor could be useful for producing a greater magnitude of change in ¹¹C-raclopride binding. Mazindol is a non-selective catecholamine reuptake inhibitor, which blocks dopamine reuptake and thus could be used as an enhancer of dopamine release by neuropsyhological tasks. To investigate basic potency of mazindol in human, we measured occupancy of the dopamine transporter and change in ¹¹C-raclopride binding using PET after single oral administration of mazindol.

Methods Two sets of PET scans were acquired on seven healthy volunteers after oral administration of placebo and 1.5 mg of mazindol. ¹¹C-raclopride was injected at 3 hours after the administration of placebo or mazindol, and ¹⁸F-FE-PE2I was injected at 5 hours. Binding potential of sub-regions of striatum was calculated by the simplified reference tissue model using cerebellum as reference region. Dopamine transporter occupancy was calculated by the % change of the binding potential of ¹⁸F-FE-PE2I, and change in extracellular dopamine levels was measured by the % change of that of ¹¹C-raclopride.

Results After oral administration of 1.5 mg of mazindol, the binding potential of ¹⁸F-FE-PE2I significantly reduced by 20 - 27 % (p < 0.01, paired t-test), indicating 20 - 27 % of dopamine transporters in the striatum was occupied by mazindol. Meanwhile, the binding potential of ¹¹C-raclopride reduced by 3 - 6%, but the reduction was not significant, indicating the change in extracellular dopamine levels by mazindol without neuropsyhological tasks was small.

Conclusions After oral administration of 1.5 mg of mazindol, dopamine transporters were occupied in a small proportion, and the change in extracellular dopamine levels was minimal.