当前位置： SCI文献检索 > BIOORGANIC & MEDICINAL CHEMISTRY期刊下所有文献 > Chiral resolution of serial potent and selective σ1 ligands and biological evaluation of (-)-[18F]TZ3108 in rodent and the nonhuman primate brain.

Chiral resolution of serial potent and selective σ1 ligands and biological evaluation of (-)-[18F]TZ3108 in rodent and the nonhuman primate brain.

Abstract：

:Twelve optically pure enantiomers were obtained using either crystallization or chiral high performance liquid chromatography (HPLC) separation methodologies to resolve six racemic sigma-1 (σ1) receptor ligands. The in vitro binding affinities of each enantiomer for σ1, σ2 receptors and vesicular acetylcholine transporter (VAChT) were determined. Out of the 12 optically pure enantiomers, five displayed very high affinities for σ1 (Ki<2nM) and high selectivity for σ1 versus σ2 and VAChT (>100-fold). The minus enantiomer, (-)-14a ((-)-TZ3108) (Ki-σ1=1.8±0.4nM, Ki-σ2=6960±810nM, Ki-VAChT=980±87nM), was chosen for radiolabeling and further in vivo evaluation in rodents and nonhuman primates (NHPs). A biodistribution study in Sprague Dawley rats showed brain uptake (%ID/gram) of (-)-[18F]TZ3108 reached 1.285±0.062 at 5min and 0.802±0.129 at 120min. NHP microPET imaging studies revealed higher brain uptake of (-)-[18F]TZ3108 and more favorable pharmacokinetics compared to its racemic counterpart. Pretreatment of the animal using two structurally different σ1 ligands significantly decreased accumulation of (-)-[18F]TZ3108 in the brain. Together, our in vivo evaluation results suggest that (-)-[18F]TZ3108 is a promising positron emission tomography (PET) tracer for quantifying σ1 receptor in the brain.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Yue X,Jin H,Luo Z,Liu H,Zhang X,McSpadden ED,Tian L,Flores HP,Perlmutter JS,Parsons SM,Tu Z

doi

10.1016/j.bmc.2017.01.017

subject

Has Abstract

pub_date

2017-02-15 00:00:00

pages

1533-1542

issue

4

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(16)31316-5

journal_volume

25

pub_type

杂志文章

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