Concentration and occupancy of dopamine transporters in cocaine abusers with [11C]cocaine and PET

Abstract

The concentration (Bmax) of the dopamine transporter (DAT) and the maximum and effective occupancies by cocaine doses of 0.1 mg/kg or 0.05 mg/kg were measured in the striatum of cocaine abusers (n = 12) by using [11C]cocaine as a radiotracer for the DAT and positron emission tomography (PET). Two methods based on a three-compartment model with one binding site (the nonlinear least squares (NLSQ) and the Farde pseudoequilibrium method) were used to estimate Bmax. Effective occupancies and maximum occupancies were calculated from the distribution volume ratios (DVR) and a three-compartment model, respectively. The NLSQ and Farde methods gave similar values of Bmax (average, 650 +/- 350 pmol/ml 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 studies, respectively. The ED50 based on the effective occupancy corresponds to 0.1 mg/kg, which is significantly smaller than the ED50 of 3 mg/kg calculated from studies in which [123]beta-CIT is displaced by cocaine. The effect on the Bmax estimate of two binding sites with different Kd's is also considered by simulation. We conclude (1) that the lack of robustness in the Bmax estimate limits the usefulness of any one 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, however, provide an estimate of the expected concentration in humans. (2) The DVR can be used as a measure of DAT occupancy without applying an explicit model.

Measurement of 5-HT1A Receptor Density and in-vivo Binding Parameters of [18F]mefway in the Nonhuman Primate

“…These data are shown in Figure 7B with all of the regions plotted on the same axis (although they were analyzed separately). A similar lack of correlation between the dopamine transporter B max and a composite binding parameter (BP P ) has been reported using [ 11 C]cocaine and serial equilibrium PET studies (Logan et al, 1997). The authors attributed the absence of correlation to a lack of robustness in their estimation of B max .…”

Quantification of PET Studies with the Very High-Affinity Dopamine D2/D3 Receptor Ligand [11C]FLB 457: Re-Evaluation of the Validity of using a Cerebellar Reference Region

“…According to Equation (9), the apparent binding potential (BP 0 ) is reduced by the concentration of receptors in the reference region (B max 0 ) relative to that in the target region (B max ), and this difference is weighted by the in vivo affinity of the radioligand (f 2 /K D ), where f 2 is the free fraction in tissue and 1/ K D is the in vitro affinity (Logan et al, 1997 Table 4. The receptor densities in the different tissues were set to those measured in post mortem human brains by Kessler et al (1993) and Hall et al (1996), and the in vivo affinities were taken from PET measurements in non-human primates by Ginovart et al (1997), for raclopride, and Delforge et al (2001), for FLB 457.…”

Development of a simultaneous PET/microdialysis method to identify the optimal dose of 11C-raclopride for small animal imaging

“…In reality, any amount of mass should alter the 11 C-raclopride BP-the issue is to define the limits of this range when both instrument and animal size are dramatically reduced relative to the human PET data used to originally develop these tracer kinetic models (i.e. Logan et al, 1997).…”