Abstract
BackgroundNeuropeptide Y (NPY) has been implicated in a wide variety of physiological processes, including feeding, learning, memory, emotion, cardiovascular homeostasis, hormone secretion, and circadian rhythms. NPY Yl receptor (NPY Y1-R) is the most widely studied NPY receptor, and is involved in many of these processes. BMS-193885 (1) was previously developed as a potent and selective NPY Y1-R antagonist, which has good systemic bioavailability and brain penetration. To evaluate the characteristics of 1 in vivo, we developed 11C-labeled BMS-193885 ([11C]1) and its desmethyl analog ([11C]2) for potential use as two new positron emission tomography (PET) tracers.Results[11C]1 was synthesized from [11C]methyl iodide using 2. [11C]2 was synthesized from [11C]phosgene using its aniline and amine derivatives. The mean ± S.D. decay-corrected radiochemical yields of [11C]1 and [11C]2 from 11CO2 at the end of radionuclide production were 23 ± 3.2% (n = 6) and 24 ± 1.5% (n = 4), respectively. In biodistribution on mice, radioactivity levels for both tracers were relatively high in the kidney, small intestine, and liver at 60 min post-injection. The radioactivity levels in the kidney, lung, and spleen of mice at 30 min post-injection with [11C]1 were significantly reduced by pretreatment with 1 (10 mg/kg), and levels of [11C]1 in the brain of mice were significantly increased by pretreatment with the P-glycoprotein and breast cancer resistance protein inhibitor elacridar (10 mg/kg). In metabolite analysis using mouse plasma, [11C]1 and [11C]2 were rapidly metabolized within 30 min post-injection, and [11C]1 was mainly metabolized into unlabeled 2 and radiolabeled components.Conclusion[11C]1 and [11C]2 were successfully synthesized with sufficient amount of radioactivity and high quality for use in vivo. Our study of [11C]1 and its desmethyl analog [11C]2 was useful in that it helped to elucidate the in vivo characteristics of 1.
Highlights
Neuropeptide Y (NPY) has been implicated in a wide variety of physiological processes, including feeding, learning, memory, emotion, cardiovascular homeostasis, hormone secretion, and circadian rhythms
To evaluate and clarify the in vivo characteristic of 1, such as its biodistribution, metabolism, and the effects of ATP-binding cassette (ABC) transporters on the whole-body uptake of its radioactivity, in this study we evaluated the in vivo characteristics of 11C-labeled BMS-193885 ([11C]1, Fig. 1) and its O-desmethyl analog ([11C]2, Fig. 1)
Dimethyl 4-(3-(3-(3-(4-(3-hydroxyphenyl)piperidin-1-yl)propyl)ureido)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (2, Fig. 1), dimethyl 4-(3-isocyanatophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (3, Fig. 1), and 3-(1-(3-aminopropyl)piperidin-4-yl)phenol (4, Fig. 1) were synthesized in-house according to procedures reported previously (Poindexter et al 2002), and were identified by nuclear magnetic resonance and high-resolution mass spectrometry to be consistent with the data described previously (Poindexter et al 2002)
Summary
Neuropeptide Y (NPY) has been implicated in a wide variety of physiological processes, including feeding, learning, memory, emotion, cardiovascular homeostasis, hormone secretion, and circadian rhythms. NPY has been implicated in a wide variety of physiological processes, including feeding (Clark et al 1984; Stanley and Leibowitz 1985; Flood and Morley 1989), learning and memory (Flood and Morley 1989), cardiovascular functions (Jacques et al 2007), and circadian rhythms (Sindelar et al 2005). A non-peptide 18F-labeled NPY Y1-R antagonist ([18F]Y1–973) was developed and demonstrated to have effective properties as a positron emission tomography (PET) tracer for imaging NPY Y1-Rs in the central nervous system (Kameda et al 2009; Hostetler et al 2011)
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