Employing in vitro metabolism to guide design of F-labelled PET probes of novel alpha-synuclein binding bifunctional compounds
Date
2021-06-30
Authors
Nwabufo, Chukwunonso
Aigbogun, Omozojie
Allen, Kevin
Madeline N. Owens
Jeremy S. Lee
Christopher P. Phenix
Krol, Ed
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Publisher
Taylor & Francis
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Type
Postprint
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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 -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.
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Keywords
Microsomal metabolism, Positron Emission Tomography, Imaging probe design, alpha-synuclein, Parkinson’s disease, Fluorine radiolabelling
Citation
Chukwunonso K. Nwabufo, Omozojie P. Aigbogun, Kevin J.H Allen, Madeline N. Owens, Jeremy S. Lee, Christopher P. Phenix & Ed S. Krol (2021). Employing in vitro metabolism to guide design of F-labelled PET probes of novel α-synuclein binding bifunctional compounds, Xenobiotica, 51:8, 885-900. 10.1080/00498254.2021.1943566
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Citation
Chukwunonso K. Nwabufo, Omozojie P. Aigbogun, Kevin J.H Allen, Madeline N. Owens, Jeremy S. Lee, Christopher P. Phenix & Ed S. Krol (2021). Employing in vitro metabolism to guide design of F-labelled PET probes of novel α-synuclein binding bifunctional compounds, Xenobiotica, 51:8, 885-900. 10.1080/00498254.2021.1943566
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DOI
10.1080/00498254.2021.1943566