Radiosynthesis and evaluation of a fluorine-18 labeled radioligand targeting vesicular acetylcholine transporter

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:28

Article

Yue, Xuyi¹  Luo, Zonghua¹  Liu, Hui¹  Kaneshige, Kota²  Parsons, Stanley M.²  Perlmutter, Joel S.^1,3  Tu, Zhude¹ 

[1] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA

[2] Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA

[3] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

关键词: Vesicular acetylcholine transporter;    Fluorine-18;    Radiolabeling;    PET imaging;   

DOI  :  10.1016/j.bmcl.2018.09.030

来源: Elsevier

【 摘 要 】

Vesicular acetylcholine transporter (VAChT) is a reliable biomarker for assessing the loss of cholinergic neurons in the brain that is associated with cognitive impairment of patients. 5-Hydrotetralin compound (+/-)-5-OH-VAT is potent (K-i = 4.64 +/- 0.32 nM) and selective for VAChT (> 1800-fold and 398-fold for sigma(1) and sigma(2) receptor, respectively) with favorable hydrophilicity (LogD = 1.78), while (-)-5-OH-VAT originally serves as the radiolabeling precursor of (-)-[F-18]VAT, a promising VAChT radiotracer with a logD value of 2.56. To evaluate (-)-5-OH-[F-18]VAT as a radiotracer for VAChT, we performed in vitro binding assay to determine the potency of the minus enantiomer (-)-5-OH-VAT and plus enantiomer (+)-5-OH-VAT, indicating that (-)-5-OH-VAT is a more potent VAChT enantiomer. Radiosynthesis of (-)-5-OH-[F-18]VAT was explored using three strategies. (-)-5-OH-[F-18]VAT was achieved with a good yield (24 +/- 6%) and high molar activity (similar to 37 GBq/mu mol, at the end of synthesis) using a microwave assisted two-step one-pot procedure that started with di-MOM protected nitro-containing precursor (-)-6. MicroPET studies in the brain of nonhuman primate (NHP) suggest that (-)-5-OH-[F-18]VAT readily penetrated the blood brain barrier and specifically accumulated in the VAChT-enriched striatum with improved washout kinetics from striatum compared to [F-18]VAT. Nevertheless, the lower target to non-target ratio may limit its use for in vivo measurement of the VAChT level in the brain.

【 授权许可】

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