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In Vivo Quantification and Parametric Images of the Cardiac ß-Adrenergic Receptor Density

¹ Service Hospitalier Frédéric Joliot, Commissariat à l’Energie Atomique/Direction des Sciences du Vivant, Orsay, France
² Merck–Lipha, Centre de Recherche de Chilly-Mazarin, Chilly-Mazarin, France

View larger version (9K): [in a new window]   FIGURE 1. Three-compartment ligand-receptor model used for analysis of CGP 12177 time–concentration curves obtained with PET. All transfer probabilities of ligand between compartments are linear, except for binding probability, which depends on local association rate constant (kon), on local free ligand concentration (F*(t)/VR), and on local concentration of unoccupied receptor sites (B'max-B*(t)). PET experimental data correspond to sum of labeled ligand in 2 tissue compartments and of fraction FV of blood concentration. B and B* = unlabeled and labeled bound ligand concentrations, respectively; B'max = receptor concentration; Ca* and F* = free ligand concentration in blood and tissue, respectively; k1 and k2 = rate constants; kon and koff = association and dissociation rate constants, respectively.

View larger version (13K): [in a new window]   FIGURE 2. Estimation of ß-adrenergic receptor density using graphic method. Experimental protocol includes 2 injections with doses D1* and D2* at times T1 and T2, respectively. Graphic method is based on measurement of 2 plateau levels at end of distribution phase (C1* and C2*). Plateaus are estimated from only portion of PET data (large •), other data (small •) being disregarded by graphic method. Receptor density is obtained from Equation 2. From current data (specific activity = 29,415 MBq/µmol, D1* = 3.09 nmol, D2* = 22.19 nmol) and using vascular fraction of 40%, receptor concentration is estimated at 18.6 pmol/mL.

View larger version (13K): [in a new window]   FIGURE 3. Example of plasma and blood ratio curves obtained with mini pigs using multiinjection protocol (Table 1, experiment 7, shows timing and injected doses). This ratio is not constant, in particular because of association of CGP 12177 with red blood cells.

View larger version (15K): [in a new window]   FIGURE 4. Example of PET time–concentration curves obtained with mini pigs using multiinjection protocol. Experimental data obtained in experiment 7 (Table 1 shows timing and injected doses) in myocardium are represented by . Solid line, which is simulated curve obtained from estimated model parameters (Table 2), is close to experimental data. This proves quality of fit obtained using 3-compartment model. PET-measured concentrations in cavity () are good estimates of blood concentration measured by sampling (dotted line) during first 10 min after injection. After this period, low concentration and heart movements lead to noisy data.

View larger version (16K): [in a new window]   FIGURE 5. Simulations of CGP 12177 kinetics performed with model parameters estimated during experiment 7 (Fig. 4). Symbols represent concentrations in free () and bound () ligand compartments. Solid line represents PET-measured concentration that is sum of concentration in the 2 tissue compartments and of fraction FV of blood concentration (dotted line, which represents in this case 52% of blood time–concentration curve shown in Fig. 4).

View larger version (110K): [in a new window]   FIGURE 6. Example of vascular fraction image estimated pixel by pixel. For each pixel, vascular fraction is estimated by dividing mean PET concentration during first minute after first injection by mean blood concentration measured in cavity during same period. Limits of high-receptor-density area observed in Figure 7 are marked by line. Highest vascular fraction is observed in heart cavities.

View larger version (90K): [in a new window]   FIGURE 7. Example of parametric image of ß-adrenergic receptor concentration. Experiment is same as in Figure 2 (legend of Fig. 2 describes doses). This image has been obtained by calculating receptor density using Equation 2, pixel by pixel and without filtering. Correction for vascular fraction is performed using Figure 6 results. No correction for partial-volume effect was performed.