Radiosynthesis and evaluation of a fluorine-18 labeled radioligand targeting vesicular acetylcholine transporter. Issue 21 (15th November 2018)

• Record Type: Journal Article
• Authors: Yue, Xuyi; Luo, Zonghua; Liu, Hui; Kaneshige, Kota; Parsons, Stanley M.; Perlmutter, Joel S.; Tu, Zhude
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 21(2018)
• Page Start: 3425
• Page End: 3430
• Publication Date: 2018-11-15
• Subjects: Vesicular acetylcholine transporter -- Fluorine-18 -- Radiolabeling -- PET imaging; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.09.030
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: An enantiomeric VAChT compound with high binding affinity was synthesized. Radiosynthesis of the potent enantiomer was achieved in a good yield. The radiotracer specifically accumulated in the VAChT-enriched striatum with quick washout kinetics. Abstract: 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 ( Ki = 4.64 ± 0.32 nM) and selective for VAChT (>1800-fold and 398-fold for σ 1 and σ 2 receptor, respectively) with favorable hydrophilicity (LogD = 1.78), while(−)-5-OH-VAT originally serves as the radiolabeling precursor of (−)-[ 18 F]VAT, a promising VAChT radiotracer with a logD value of 2.56. To evaluate(−)-5-OH-[ 18 F]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-[ 18 F]VAT was explored using three strategies.(−)-5-OH-[ 18 F]VAT was achieved with a good yield (24 ± 6%) and high molar activity (∼37 GBq/ µ 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-[ 18 F]VAT readily penetrated the blood brain barrier and specifically accumulated in the VAChT-enriched striatum with improved washout kinetics from striatum compared to [ 18 F]VAT. Nevertheless, the lower target to non-target ratio may limit its use for in vivo measurement of the VAChT level in the brain.