Concentration of dopamine transporters: to Bmax or not to Bmax?

We read with interest the paper by Logan et al. (1997) entitled ''Concentration and Occupancy of Dopamine Transporters in Cocaine Abusers With [11C]Cocaine and PET'' in the December issue of Synapse. The conclusion of the Logan paper was that estimates of the available number of receptor sites, BЈ max , from PET data are inherently unreliable and should, in general, be avoided in favor of the more robust measure , distribution volume ratio (DVR ϭ BЈ max /K D ϩ 1). They based their conclusions primarily on the variability that they found in BЈ max using either the pseudo-equilibrium (PSE) method (Farde et al., 1989) or nonlinear least-squares (NLSQ) fitting of the three-compartment model as compared to the variability in DVR calculated from their own graphical method (Logan et al., 1990). The Farde method has been suspect for some time and, as Logan et al. show, it is highly sensitive to the choice of particular pseudo-equilibrium point. Neither are we surprised about the poor performance of the NLSQ method for estimating BЈ max from a single injection, for reasons stated below, and we applaud Logan et al. for demonstrating the shortcomings in these methods. However, as support for their position against using BЈ max , they also cited variability that we observed recently (Morris et al., 1996a) in density of the dopamine transporter (DAT) in rhesus monkeys. In that study we used a more sophisticated and theoretically sound technique of three injections of 11 C-CFT followed by NLSQ fitting of all of the dynamic data simultaneously. Logan et al. further reasoned that BЈ max should correlate with BЈ max /K D. Since in the results for normal animals in our paper it did not, they asserted that the only parameter that we have really measured reliably is BЈ max /K D , which was fairly well preserved across 3 experimental animals. Unfortunately, the Brookhaven group ignored more compelling intra-subject data (see animal A) in our paper, which showed that when pre-synaptic neurons were destroyed by MPTP, both the animal's BЈ max (122 nM pre-MPTP, 13 nM post-MPTP) and BЈ max /K D (3.5 pre-, 0.28 post-) dropped precipitously, whereas the K D remained nearly constant (34 nM pre-, 46.6 nM post-). Thus, when a (MPTP) lesion was specifically directed at the density of transporters on neurons terminating in the striatum, the change in parameter values (in repeated measures) reflected this …