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Increased Brain Exposure of an Alpha-Synuclein Fibrillization Modulator by Utilization of an Activated Ester Prodrug Strategy.

Abstract：

:Previous work in our laboratories has identified a series of peptidomimetic 2-pyridone molecules as modulators of alpha-synuclein (α-syn) fibrillization in vitro. As a first step toward developing molecules from this scaffold as positron emission tomography imaging agents, we were interested in evaluating their blood-brain barrier permeability in nonhuman primates (NHP) in vivo. For this purpose, 2-pyridone 12 was prepared and found to accelerate α-syn fibrillization in vitro. Acid 12, and its acetoxymethyl ester analogue 14, were then radiolabeled with 11C ( t1/2 = 20.4 min) at high radiochemical purity (>99%) and high specific radioactivity (>37 GBq/μmol). Following intravenous injection of each compound in NHP, a 4-fold higher radioactivity in brain was observed for [11C]14 compared to [11C]12 (0.8 vs 0.2 SUV, respectively). [11C]14 was rapidly eliminated from plasma, with [11C]12 as the major metabolic product observed by radio-HPLC. The presented prodrug approach paves the way for future development of 2-pyridones as imaging biomarkers for in vivo imaging of α-synuclein deposits in brain.

journal_name

ACS Chem Neurosci

journal_title

ACS chemical neuroscience

authors

Cairns AG,Vazquez-Romero A,Mahdi Moein M,Ådén J,Elmore CS,Takano A,Arakawa R,Varrone A,Almqvist F,Schou M

doi

10.1021/acschemneuro.8b00236

subject

Has Abstract

pub_date

2018-11-21 00:00:00

pages

2542-2547

issue

11

issn

1948-7193

journal_volume

9

pub_type

杂志文章

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