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

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.

[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.

[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.