A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy

Ho Young Kim, Wai Kit Chia, Chia Ju Hsieh, Dinahlee Saturnino Guarino, Thomas J.A. Graham, Zsofia Lengyel-Zhand, Mark Schneider, Cosette Tomita, Marshall G. Lougee, Hee Jong Kim, Vinayak V. Pagar, Hsiaoju Lee, Catherine Hou, Benjamin A. Garcia, E. James Petersson, Jennifer O’Shea, Paul T. Kotzbauer, Chester A. Mathis, Virginia M.Y. Lee, Kelvin C. LukRobert H. Mach

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Abnormal α-synuclein (α-syn) aggregation characterizes α-synucleinopathies, including Parkinson’s disease (PD) and multiple system atrophy (MSA). However, no suitable positron emission tomography (PET) radiotracer for imaging α-syn in PD and MSA exists currently. Our structure-activity relationship studies identified 4-methoxy-N-(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)benzamide (4i) as a PET radiotracer candidate for imaging α-syn. In vitro assays revealed high binding of 4i to recombinant α-syn fibrils (inhibition constant (Ki) = 6.1 nM) and low affinity for amyloid beta (Aβ) fibrils in Alzheimer’s disease (AD) homogenates. However, [3H]4i also exhibited high specific binding to AD, progressive supranuclear palsy, and corticobasal degeneration tissues as well as PD and MSA tissues, suggesting notable affinity to tau. Nevertheless, the specific binding to pathologic α-syn aggregates in MSA post-mortem brain tissues was significantly higher than in PD tissues. This finding demonstrated the potential use of [11C]4i as a PET tracer for imaging α-syn in MSA patients. Nonhuman primate PET studies confirmed good brain uptake and rapid washout for [11C]4i.

Original languageEnglish
Pages (from-to)12185-12202
Number of pages18
JournalJournal of Medicinal Chemistry
Volume66
Issue number17
DOIs
StatePublished - Sep 14 2023

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