Measurement of benzodiazepine receptor number and affinity in humans using tracer kinetic modeling, positron emission tomography, and [11C]flumazenil

Julie C. Price, Helen S. Mayberg, Robert F Dannals, Alan A. Wilson, Hayden T. Ravert, Bernard Sadzot, Zachary Rattner, Allyn Kimball, Marc A. Feldman, J. James Frost

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Abstract

Kinetic methods were used to obtain regional estimates of benzodiazepine receptor concentration (Bmax) and equilibrium dissociation constant (Kd) from high and low specific activity (SA) [11C]flumazenil ([11C] 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 inhibition study (pretreatment with 0.15 mg/kg of flumazenil) was performed on one of the volunteers, which resulted in an average gray matter K1/k2 estimate of 0.68 ± 0.08 ml/ml (linear three-compartment model, 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 the inhibition K1/k2 ratio and each volunteer's mean f1 value (f2 across volunteers = 0.72 ± 0.03 ml/ml). Three methods (Methods I-III) were examined. Method I determined five kinetic parameters simultaneously [K1, k2, K3 ( = konf2Bmax), k4, and Konf2/SA] with no a priori constraints. An average kon value of 0.030 ± 0.003 nM-1 min-1 was estimated for receptor-rich regions using Method I. In Methods II and III, the konf2/SA parameter was specifically constrained using the Method I value of kon and the volunteer's values of f2 and low SA (Ci/μmol) Four parameters were determined simultaneously using Method II. In Method III. K1/k2 was fixed to the inhibition value and only three parameters were estimated. Method I provided the most variable results and convergence problems for regions with low receptor binding. Method II provided results that were less variable but very similar to the Method I results, without convergence problems. However, the K1/k2 ratios obtained by Method II ranged from 1.07 in the occipital cortex to 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 /, and resulted in parameters with considerably lower variability. The average Bmax values obtained using Method III were 100 ± 25 nM in the occipital cortex, 64 ± 18 nM in the cerebellum, and 38 ± 5.5 nM in the thalamus; the average Kd was 8.9 ± 1.0 nM (five brain regions).

Original languageEnglish (US)
Pages (from-to)656-667
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume13
Issue number4
Publication statusPublished - 1993

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Keywords

  • [C]Flumazenil
  • Benzodiazepine receptors
  • Human brain
  • Kinetic modeling
  • Positron emission tomography

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Neuroscience(all)

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