Design, Radiosynthesis, and Evaluation of New Fluorinated Analogs of MeDAS for Myelin PET Imaging

Abstract

Positron emission tomography (PET) imaging of the myelin sheath is a powerful tool to investigate multiple sclerosis, monitor its evolution, and support drug development. Radiotracers based on N,N-dimethylaminostilbene (MeDAS) fluorinated analogs have been designed for myelin PET imaging but were never translated to humans. We have synthesized three original fluorinated analogs of MeDAS with low metabolic rates for which binding to myelin in a healthy rat brain was demonstrated by fluorescence microscopy. A tosyl precursor was synthesized for the lead compound PEGMeDAS and automated fluorine-18 radiolabeling afforded [18F]­PEGMeDAS in 25 ± 5% radiochemical yield and 102 ± 15 GBq/μmol molar activity. Biodistribution in healthy rats demonstrated the brain penetration with low penetration of radiometabolites. However, E to Z isomerization observed in plasma hampers further investigations of this family of molecules and requires complementary data on the in vivo behavior of the Z isomer.

Diagnostic and Therapeutic Radiopharmaceuticals: A “Hot” Topic

“…In vivo biodistribution of [ 18 F]11 (Figure 1) demonstrated a high brain uptake. 12 Another emerging therapeutic target for neurodegenerative diseases is activated Abelson non-receptor tyrosine kinase (c-Abl), which is believed to play a role in the post-translational modification of α-synuclein and represents a key step in the disease-associated aggregation of this protein. The manuscript by Windhorst et al describes a series of studies aimed at developing a PET radiotracer for imaging c-Abl.…”

“…Fluorinated analogues of MeDAS with low metabolic rates were discovered, for which binding to myelin in a healthy rat brain was demonstrated by fluorescence microscopy. In vivo biodistribution of [ 18 F] 11 (Figure ) demonstrated a high brain uptake …”