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Synthesis and Biodistribution of Radiolabeled ₇ Nicotinic Acetylcholine Receptor Ligands

¹ Johns Hopkins University, Baltimore, Maryland
² AstraZeneca, Wilmington, Delaware

View larger version (17K): [in a new window]   FIGURE 1. 11C-Labeled ligands: radiosyntheses. RC = radiochemical yield; SA = specific activity; EOB = end of bombardment.

View larger version (20K): [in a new window]   FIGURE 2. 125I-Labeled ligands: radiosyntheses. DMSO = dimethyl sulfoxide; RC = radiochemical yield; SA = specific activity.

View larger version (14K): [in a new window]   FIGURE 3. Brain kinetics of 3. Time course of uptake of 3 is presented in cerebellum (low 7-nAChR content), cortex (intermediate 7-nAChR content), and hippocampus (target tissue). Although up to 80 min after injection there is less uptake demonstrated in hippocampus than in cerebellum or cortex, hippocampal uptake remains constant and persists over time.

View larger version (24K): [in a new window]   FIGURE 4. Binding specificity of 3. A significant decrease in uptake of 3 was demonstrated in cerebellum, hippocampus, striatum, and cortex on pretreatment with 10 mg/kg nicotine to block 7-nAChR. Because blockade was demonstrated within each region, including cerebellum, a nontarget region, we cannot conclude that the degree of blockade demonstrated can all be attributed to specific binding.

View larger version (19K): [in a new window]   FIGURE 5. Brain kinetics of 4. Time course of uptake of 4 is presented in cerebellum, cortex, hippocampus, and superior colliculus (another target tissue). Note that higher uptake of 4 is demonstrated in target tissues over the entire time course of this study.

View larger version (37K): [in a new window]   FIGURE 6. Binding specificity of 4. A significant decrease in uptake of 4 was obtained in all regions tested except for cerebellum, which has low 7-nAChR content, on pretreatment with increasing concentrations of unlabeled 4. These findings suggest an element of specific binding of 4 to 7-nAChR. Sup. colliculus = superior colliculus.