Summary: Carbon-l l·labeled flu maze nil combined with positron emission tomography (PET) was used to mea sure the concentration (BmaX> of the benzodiazepine (Bz) receptor in the brain and its equilibrium dissociation con stant (KD) for flumazenil in five normal sUbjects. The steady-state approach was used injecting the tracer as a bolus of high specific activity. In each subject two studies were carried out. The first study was performed at essen tially zero receptor occupancy, the tracer alone study. The second study was performed at a steady-state recep tor occupancy of about 50%, achieved by a prolonged constant infusion of nonlabeled ("cold") flumazenil starting 2 h before the bolus tracer injection and continu ing until the end of the scanning period. In this second study the free concentration of unmetabolized flumazenil in plasma water was measured in mUltiple blood samples. The observed tissue and plasma tracer curves, calibrated in the same units of radioactivity per millimeter, were an alyzed in two ways: (a) by the noncompartmental (stoCarbon-II-labeled flumazenil has been intro duced as a positron emission tomography (PET) ligand for studying central benzodiazepine (Bz) re ceptors in the human brain (Ehrin et aI., 1984; Ma ziere et aI., 1984). Flumazenil is a Bz receptor an tagonist that can be injected at doses that result in a significant degree of occupation of receptor sites with negligible clinical effects in drug-naive sub jects. Flumazenil has the properties of a good PET ligand: (a) fairly rapid metabolism in the liver to a hydrophilic molecule that does not cross the blood- In general, the approach has been to record a dynamic set of tomograms, describing the uptake and subsequent washout of the tracer following bo lus injection of the tracer at high and low specific activities. In the case of a low-specific activity study the changing concentrations of unlabeled flu maze nil will result in a changing receptor occu pancy throughout the investigation. Various ap proaches have been proposed to handle this non steady state, for example, by calculating the bound l free ratio of the tracer during a time interval of assumed near-equilibrium, the so-called pseu doequilibrium approach (Pappata et aI., 1988), or by fitting the nonlinear differential equations resulting from the non-steady state (Blomquist et aI., 1990;

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