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SPECT Quantification of Benzodiazepine Receptor Concentration Using a Dual-Ligand Approach

¹ Psychiatric Neuroimaging Unit, Division of Neuropsychiatry, Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland; and ² INSERM, E340, Grenoble, France

View larger version (20K): [in a new window]   FIGURE 1.  Three-compartment model used to fit SPECT data. This model contains 2 components for labeled and unlabeled ligands with individual parameters for IMZ and FMZ. Compartments Cp*(t) and Cp(t) represent unchanged plasma 123I-IMZ and FMZ, respectively; Mf+ns(t) represents free and nonspecifically bound ligand, and Ms(t) represents specifically bound ligand. Parameters K1 and k'2 are associated with exchanges between plasma and free/nonspecifically bound ligand compartment. B'max represents concentration of receptors available for binding and is defined as the common parameter of the model; kon and koff are association and dissociation rate constants, respectively; and VR is volume of the reaction, which accounts for tissue inhomogeneity (26). Consequently, only the apparent equilibrium dissociation constant, KdVR, can be estimated. Kd is equilibrium dissociation constant, defined as the ratio of koff to kon. Parameter FV represents the fraction of blood present in tissue volume and was fixed at 0.04 (13,27,28).

View larger version (24K): [in a new window]   FIGURE 2.  Time courses of 11C-FMZ and 123I-IMZ plasma components obtained from previous study for 7 healthy volunteers (14). Time courses of unchanged plasma levels of both tracers are linked by the following relationship: 11C-FMZ = (f1FMZ/f1IMZ) x (123I-IMZ/(0.72 e–0.08[t-6.3])), where f1FMZ = 0.5 and f1IMZ = 0. 33.

View larger version (30K): [in a new window]   FIGURE 3.  Example with 1 volunteer of a coupled fit obtained among 8 ROIs placed on gray matter (1), whole brain (2), white matter (3), pons (4), occipital cortex (5), frontal cortex (6), temporal cortex (7), and cerebellum (8). Common parameters were estimated simultaneously, and resulting values were used as constants to simplify the model.

View larger version (31K): [in a new window]   FIGURE 4.  Compartmental analysis allows simulation of time courses for each compartment: free/nonspecifically bound and specifically bound ligand for 123I-IMZ (A and B) and FMZ (C and D). The first column corresponds to protocol 1 and the second column corresponds to protocol 2. Only the labeled input function of the model is represented here. Estimated IMZ model parameters were as follows: for A and C, B'max = 53 ± 1 pmol/mL, K1 = 0.54 ± 0.01 min–1, k'2 = 0.19 ± 0.01 min–1, kon/VR = 0.071 ± 0.003 mL/pmol·min, koff = 0.18 ± 0.01 min–1; and for B and D, B'max = 44 ± 2 pmol/mL, K1 = 0.44 ± 0.01 min–1, k2 = 0.20 ± 0.01 min–1, kon/VR = 0.100 ± 0.003 mL/pmol·min, koff = 0.24 ± 0.01 min–1.

View larger version (11K): [in a new window]   FIGURE 5.  (A) Comparison across regions and volunteers between distribution volume values estimated using 3-compartment model parameters (DVT) and 2-compartment model parameters (DVT''). Quasiidentity line was obtained between values. (B) Comparison between B'max values and their corresponding DVT'' values estimated with 2-compartment model.

View larger version (18K): [in a new window]   FIGURE 6.  Direct comparison between B'max values obtained in same volunteer with PET multiinjection approach and with SPECT dual-ligand approach. Dashed line corresponds to identity line.