CONCENTRATION AND OCCUPANCY OF DOPAMINE TRANSPORTERS IN COCAINE ABUSERS WITH [C-11] COCAINE AND PET

The concentration (Bmax) of the dopamine transporter (DAT) and the max imum and effective occupancies by cocaine doses of 0.1 mg/kg or 0.05 m g/kg were measured in the striatum of cocaine abusers (n = 12) by usin g [C-11]cocaine as a radiotracer for the DAT and positron emission tom ography (PET). Two methods based on a three-compartment model with one binding site (the nonlinear least squares (NLSQ) and the Farde pseudo equilibrium method) were used to estimate Bmax. Effective occupancies and maximum occupancies were calculated from the distribution volume r atios (DVR) and a three-compartment model, respectively. The NLSQ and Farde methods gave similar values of Bmax (average, 650 +/- 350 pmol/m l and 776 +/- 400 pmol/ml, respectively), but the individual estimates of Bmax were found to be very sensitive to small variations in other model parameters and were not correlated with the parameter Bmax/Kd (r = .07). The average maximum (and effective) occupancies were found to be 67% (50%) and 52% (39%) for the 0.1-mg/kg and the 0.05-mg/kg studi es, respectively. The ED50 based on the effective occupancy correspond s to 0.1 mg/kg, which is significantly smaller than the ED50 Of 3 mg/k g calculated from studies in which [I-123] beta-CIT is displaced by co caine. The effect on the Bmax estimate of two binding sites with diffe rent Kd's is also considered by simulation. We conclude (1) that the l ack of robustness in the Bmax estimate limits the usefulness of any on e subject's Bmax and suggests that the combination parameter Bmax/Kd ( or the DVR), which has been used extensively, is a more stable measure of free receptor/ transporter concentration. The average Bmax may, ho wever, provide an estimate of the expected concentration in humans. (2 ) The DVR can be used as a measure of DAT occupancy without applying a n explicit model. (C) 1997 Wiley-Liss, Inc.(dagger)