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In Vivo Labeling of Endothelin Receptors with [¹¹C]L-753,037: Studies in Mice and a Dog

Sasa Aleksic, Zsolt Szabo, Ursula Scheffel, Hayden T. Ravert, William B. Mathews, Levente Kerenyi, Paige A. Rauseo, Raymond E. Gibson, H. Donald Burns and Robert F. Dannals

Division of Nuclear Medicine, Department of Radiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland; and Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania

View larger version (11K): [in a new window]   FIGURE 1. Structures of ET receptor antagonists. L-753,037 exhibits 7-fold higher affinity for ETA receptor than for ETB receptor. L-753,164 is profoundly ETA selective (ETA/ETB = >10,000).

View larger version (16K): [in a new window]   FIGURE 2. Distribution of [11C]L-753,037 in various organs of mice at different times after intravenous injection. Data are presented as mean values of %ID/g tissue ± SEM; n = 3 mice.

View larger version (26K): [in a new window]   FIGURE 3. Inhibition of [11C]L-753,037 binding in different mouse organs by 1 mg/kg L-753,164, an ETA receptor inhibitor, and L-753,037, a mixed ETA/ETB receptor blocker, 60 min after intravenous tracer administration. Drugs were injected intraperitoneally 30 min before tracer injection. Data are mean ± SEM; numbers of animals are in parentheses. **P < 0.001.

View larger version (11K): [in a new window]   FIGURE 4. Dose-dependent inhibition of [11C]L-753,037 binding to ET receptors in mouse heart by selective ETA antagonist L-753,164. Antagonist was injected intraperitoneally 30 min before tracer injection; 11C radioactivity was measured 30 min after intravenous administration. n = 3 mice for each dose level. Data are presented as mean ± SEM.

View larger version (27K): [in a new window]   FIGURE 5. Comparison of effects of different doses (0.1–10 mg/kg, administered 30 min before tracer injection) of ETA-specific inhibitor L-753,164 and mixed ETA/ETB inhibitor L-753,037 on radioactivity concentrations in mouse heart 30 min after intravenous injection of [11C]L-753,037. Data are percentages (±SEM) of saline controls; n = 3–5. **P < 0.001.

View larger version (23K): [in a new window]   FIGURE 6. PET images of dog heart 55–95 min after injection of [11C]L-753,037 without (left) and with (middle) preinjection of 1 mg/kg unlabeled L-753,164, a selective ETA antagonist. There is significant reduction of [11C]L-753,037 accumulation in wall of heart (P < 0.001) at 30 min after tracer administration. For comparison, perfusion scan with [11C]MTP is also shown (right).

View larger version (42K): [in a new window]   FIGURE 7. Time–activity curves of [11C]L-753,037 in ventricular cavity and lateral wall of dog heart and lungs before and after intravenous injection of 1 mg/kg L-753,164 (ETA antagonist).