氟代新戊二醇侧链对二苯乙烯淀粉样β PET 配体生物学特性的影响。

Effects of F-fluorinated neopentyl glycol side-chain on the biological characteristics of stilbene amyloid-β PET ligands.

机构信息

Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan.

出版信息

Nucl Med Biol. 2021 Mar-Apr;94-95:38-45. doi: 10.1016/j.nucmedbio.2020.12.008. Epub 2021 Jan 15.

DOI:10.1016/j.nucmedbio.2020.12.008

PMID:33493787

Abstract

INTRODUCTION

The 2,2-dihydroxymethyl-1-[F]fluoropropane group, also called F-labelled neopentyl glycol side-chain, is a novel F-labelling group for positron emission tomography (PET) imaging agents. The aim of using this group is to develop simple purification with solid-phase extraction without high-performance liquid chromatography. However, the effects of the neopentyl F-labelling group on the characteristics of brain imaging agents are unknown. Here, we added this side-chain to compounds with an aminostilbene structure to evaluate their effects on the biological properties of aminostilbene as an amyloid-β (Aβ) radioligand.

METHODS

Biodistributions of four novel F-labelled stilbene compounds with different lengths of polyethylene glycol (PEG) linkers, called [F]Cpd-0, -1, -2, and -4, (PEG = 0, 1, 2, and 4), and [F]AV-1 in normal mice were evaluated. Metabolite analysis of [F]Cpd-0 and -1 was performed with mouse plasma and brain. A competitive binding assay of [F]AV-1 binding to Aβ fibrils was performed to determine the binding properties of the compounds.

RESULTS

[F]Cpd-0, -1, and -2 demonstrated moderate initial brain uptake in mice (3.1-4.2% injected dose/g at 2 min post-injection) followed by fast clearance, and in vivo defluorination of these compounds was negligible. [F]Cpd-4 exhibited low brain uptake and high bone uptake. Compared with [F]Cpd-1, the percentage of [F]Cpd-0 in mouse brain was high at 10 min post-injection. A competitive binding assay revealed partial interference effects by the neopentyl glycol side-chain on binding of stilbene compounds to Aβ fibrils.

CONCLUSIONS

Aminostilbene compounds with two or fewer PEG linkers containing an F-labelled neopentyl glycol side-chain demonstrated preferable pharmacokinetic properties as a brain imaging radioligand in normal mice. These side-chains can be used as an alternative labelling group for imaging agents targeting the brain.

摘要

简介

2,2-二羟甲基-1-[F]氟丙基，也称为 F 标记的新戊二醇侧链，是正电子发射断层扫描（PET）成像剂的新型 F 标记基团。使用该基团的目的是开发无需高效液相色谱即可通过固相萃取进行简单纯化的方法。然而，新戊基 F 标记基团对脑成像剂特性的影响尚不清楚。在这里，我们将此侧链添加到具有氨基二苯乙烯结构的化合物中，以评估其作为淀粉样蛋白-β（Aβ）放射性配体对氨基二苯乙烯生物性质的影响。

方法

评估了四种具有不同长度聚乙二醇（PEG）接头的新型 F 标记二苯乙烯化合物[F]Cpd-0、-1、-2 和-4（PEG=0、1、2 和 4）和[F]AV-1 在正常小鼠体内的分布。用小鼠血浆和脑进行[F]Cpd-0 和-1 的代谢产物分析。进行[F]AV-1 与 Aβ 纤维结合的竞争结合测定，以确定化合物的结合特性。

结果

[F]Cpd-0、-1 和-2 在小鼠中显示出适度的初始脑摄取（注射后 2 分钟内为 3.1-4.2% 注入剂量/克），随后清除速度很快，并且这些化合物的体内脱氟作用可以忽略不计。[F]Cpd-4 表现出低脑摄取和高骨摄取。与[F]Cpd-1 相比，[F]Cpd-0 在注射后 10 分钟在小鼠脑中的百分比较高。竞争结合测定显示新戊二醇侧链对二苯乙烯化合物与 Aβ 纤维结合的结合具有部分干扰作用。