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

Abstract

1. 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.

2. 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.

3. 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.

Keywords:

• Microsomal metabolism
• Positron Emission Tomography
• Imaging probe design
• alpha-synuclein
• Parkinson’s disease

Disclosure statement

No potential conflict of interest was reported by the author(s)

Additional information

Funding

This work was supported by Natural Sciences and Engineering Research Council of Canada; Sylvia Fedoruk Canadian Centre for Nuclear Innovation; College of Pharmacy and Nutrition Graduate Scholarship; Department of Chemistry Graduate Scholarship.