Employing in vitro metabolism to guide design of F-labelled PET probes of novel α-synuclein binding bifunctional compounds.

Abstract

A challenge in the development of novel 18F-labelled positron emission tomography (PET) imaging probes is identification of metabolically stable sites to incorporate the 18F radioisotope. Metabolic loss of 18F from PET probes in vivo can lead to misleading biodistribution data as displaced 18F can accumulate in various tissues.In this study we report on in vitro hepatic microsomal metabolism of novel caffeine containing bifunctional compounds (C8-6-I, C8-6-N, C8-6-C8) that can prevent in vitro aggregation of α-synuclein, which is associated with the pathophysiology of Parkinson's disease. The metabolic profile obtained guided us to synthesize stable isotope 19F-labelled analogues in which the fluorine was introduced at the metabolically stable N7 of the caffeine moiety.An in vitro hepatic microsomal metabolism study of the 19F-labelled analogues resulted in similar metabolites to the unlabelled compounds and demonstrated that the fluorine was metabolically stable, suggesting that these analogues are appropriate PET imaging probes. This straightforward in vitro strategy is valuable for avoiding costly stability failures when designing radiolabelled compounds for PET imaging.

• Authors: Chukwunonso K Nwabufo, Omozojie P Aigbogun, Kevin J H Allen, Madeline N Owens, Jeremy S Lee, Christopher P Phenix, Ed S Krol
• Journal: Xenobiotica; the fate of foreign compounds in biological systems (Xenobiotica) Vol. 51 Issue 8 Pg. 885-900 (Aug 2021) ISSN: 1366-5928 [Electronic] England
• PMID: 34187286 (Publication Type: Journal Article)

Chemical References

• Fluorine Radioisotopes
• alpha-Synuclein

Topics

• Fluorine Radioisotopes
• Positron-Emission Tomography
• Tissue Distribution
• alpha-Synuclein