Synthesis and Biological Evaluation of 10‐11C‐Dihydrotetrabenazine as a Vesicular Monoamine Transporter 2 Radioligand. Issue 5 (3rd February 2014)

• Record Type: Journal Article
• Authors: Li, Xiaomin; Chen, Zhengping; Tang, Jie; Liu, Chunyi; Zou, Pei; Huang, Hongbo; Tan, Cheng; Yu, Huixin
• Is Part Of: Archiv der Pharmazie. Volume 347:Issue 5(2014:May)
• Page Start: 313
• Page End: 319
• Publication Date: 2014-02-03
• Subjects: Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.201300307
• Languages: English
• ISSNs: 0365-6233

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ardp201300307-sec-0001" sec-type="section"> <p>In this study, we synthesized a new carbon‐11‐labeled radiotracer, 10‐<sup>11</sup>C‐dihydrotetrabenazine (10‐<sup>11</sup>C‐DTBZ), and evaluated its potential as a vesicular monoamine transporter 2 (VMAT2) radioligand. The radiolabeled precursor 10‐<italic>O</italic>‐desmethyl‐dihydrotetrabenazine (10‐<italic>O</italic>‐desmethyl‐DTBZ) was prepared with a six‐step reaction using 3‐methoxy‐4‐benzyloxybenzaldehyde as starting material. 10‐<sup>11</sup>C‐DTBZ was synthesized by heating 1.0 mg of 10‐hydroxy precursor and <sup>11</sup>C‐methyl iodide in the presence of 0.3 mL of dimethyl sulfoxide and 4.0 µL of 3 N KOH at room temperature for 3 min. After purification by solid phase extraction using an alumina Sep‐Pak cartridge, the final 10‐<sup>11</sup>C‐DTBZ product was obtained with a radiochemical purity of >99% and an uncorrected radiochemical yield of 18–26% (end of bombardment (EOB), <italic>n</italic> = 6). The overall synthesis time was approximately 20 min from the EOB to release of the product for quality control. Using small‐animal positron emission tomography (microPET), the striatum of normal rats was found to exhibit symmetrical labeling (ST<sub>R</sub>/ST<sub>L</sub> = 0.98 ± 0.05, <italic>n</italic> = 3) and the highest uptake of radioactivity (striatum/cerebellum, ST/CB = 2.89 ± 0.31 at 30–60 min, <italic>n</italic> = 3). In contrast, rats with 6‐hydroxydopamine unilateral lesions yielded asymmetrical striatal images with a higher 10‐<sup>11</sup>C‐DTBZ concentration on the unlesioned side (ST<sub>unlesioned</sub>/CB = 2.53 ± 0.18, at 30–60 min, <italic>n</italic> = 3) compared with the lesioned side (ST<sub>lesioned</sub>/CB = 1.26 ± 0.10, <italic>n</italic> = 3). These results suggest that 10‐<sup>11</sup>C‐DTBZ may represent a promising PET radiotracer for imaging VMAT2.</p> </sec> </abstract>