Radiosynthesis and in vivo evaluation of 11C-labeled BMS-193885 and its desmethyl analog as PET tracers for neuropeptide Y1 receptors

Background: 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 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.
Keywords: Carbon-11, Positron emission tomography, Neuropeptide Y1 receptor,
BMS-193885

書誌情報

EJNMMI Radiopharmacy and Chemistry

巻 4, 号 4, 発行日 2019-02

出版者

Springer

ISSN

収録物識別子タイプ

ISSN

収録物識別子

2365-421X

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識別子タイプ

DOI

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Ver.1

2023-05-15 18:57:07.616210

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