Neuropeptide Y (NPY) is abundantly distributed in the peripheral and central nervous system (CNS) and is involved in the control of sympathetic nervous system activity, immune function, central regulation of energy balance and food intake,stress, anxiety, mood, and cognition[3]. JNJ-31020028 is a novel high affinity and low molecular weight Y2 receptor antagonist. NPY inhibits hypothalamic NE release through the Y2 receptor, acting at both the NE terminal and cell body region ,and Y2 antagonists increase NE release from hypothalamic synaptosomes[4]. JNJ-31020028 (15 mg/kg, s.c.) did reverse the anxiogenic effects of withdrawal from a single bolus dose of alcohol on the elevated plus-maze, confirming the anxiolytic-like properties of NPY Y2 antagonism[5]. The compound had poor oral bioavailability (6%) but high subcutaneous bioavailability (100%).Subcutaneous dosing was the preferred route for several of the models described in this paper and yielded good plasma levels (Cmax 4.35μmol/l) and fast absorption with a 0.83-h half-life[6].In autoradiography studies, N-(11)C-methyl-JNJ-31020028 receptor binding sites were observed primarily in the hippocampus and were inhibited by unlabeled JNJ-31020028. In PET studies, N-(11)C-methyl-JNJ-31020028 was metabolized slowly in the bloodstream, with 25% of the (11)C-labeled parent compound remaining 30 min after injection. PET imaging showed baseline binding potentials of 0.64 ± 0.07 in the thalamus, 0.55 ± 0.02 in the caudate, and 0.49 ± 0.03 in the hippocampus. Graphical reference region analyses demonstrated that N-(11)C-methyl-JNJ-31020028 binding was reversible; infusion of unlabeled JNJ-31020028 markedly displaced the PET radioligand from binding sites in the hippocampus, thalamus, caudate nucleus, and cerebellum but not in the corpus callosum, which served as reference region for nonspecific binding[7].
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