MEASUREMENT OF BENZODIAZEPINE RECEPTOR NUMBER AND AFFINITY IN HUMANS USING TRACER KINETIC MODELING, POSITRON EMISSION TOMOGRAPHY, AND [C-11] FLUMAZENIL

Kinetic methods were used to obtain regional estimates of benzodiazepi ne receptor concentration (B(max)) and equilibrium dissociation consta nt (K(d)) from high and low specific activity (SA) [C-11]flumazenil ([ C-11] Ro 15-1788) positron emission tomography studies of five normal volunteers. The high and low SA data were simultaneously fit to linear and nonlinear three-compartment models, respectively. An additional i nhibition study (pretreatment with 0.15 mg/kg of flumazenil) was perfo rmed on one of the volunteers, which resulted in an average gray matte r K1/k2 estimate of 0.68 +/- 0.08 ml/ml (linear three-compartment mode l, nine brain regions). The free fraction of flumazenil in plasma (f1) was determined for each study (high SA f1: 0.50 +/- 0.03; low SA f1: 0.48 +/- 0.05). The free fraction in brain (f2) was calculated using t he inhibition K1/k2 ratio and each volunteer's mean f1 value (f2 acros s volunteers = 0.72 +/- 0.03 ml/ml). Three methods (Methods I-III) wer e examined. Method I determined five kinetic parameters simultaneously [K1, k2, k3 (= k(on)f2B(max)), k4, and k(on)f2/SA] with no a priori c onstraints. An average k(on) value of 0.030 +/- 0.003 nM-1 min-1 was e stimated for receptor-rich regions using Method I. In Methods II and I II, the k(on)f2/SA parameter was specifically constrained using the Me thod I value of k(on) and the volunteer's values of f2 and low SA (Ci/ mumol). Four parameters were determined simultaneously using Method II . In Method III, K1/k2 was fixed to the inhibition value and only thre e parameters were estimated. Method I provided the most variable resul ts and convergence problems for regions with low receptor binding. Met hod II provided results that were less variable but very similar to th e Method I results, without convergence problems. However, the K1/k2 r atios obtained by Method II ranged from 1.07 in the occipital cortex t o 0.61 in the thalamus. Fixing the K1/k2 ratio in Method III provided a method that was physiologically consistent with the fixed value of f 2 and resulted in parameters with considerably lower variability. The average B(max) values obtained using Method III were 100 +/- 25 nM in the occipital cortex, 64 +/- 18 nM in the cerebellum, and 38 +/- 5.5 n M in the thalamus; the average K(d) was 8.9 +/- 1.0 nM (five brain reg ions).