Employing <i>in vitro</i> metabolism to guide design of F-labelled PET probes of novel α-synuclein binding bifunctional compounds
Creators: name: Nwabufo, Chukwunonso K.
name: Aigbogun, Omozojie P.
name: Allen, Kevin J.H
name: Owens, Madeline N.
name: Lee, Jeremy S.
name: Phenix, Christopher P.
name: Krol, Ed S.
Publisher: name: Taylor & Francis
Year: 2021
Subjects: subject: Biochemistry
subject: Medicine
subject: Cell Biology
subject: Neuroscience
subject: Physiology
subject: FOS: Biological sciences
subject: Pharmacology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: Cancer
subject: 111714 Mental Health
subject: FOS: Health sciences
subject: 110309 Infectious Diseases
subject: Computational Biology

description: A challenge in the development of novel <sup>18</sup>F-labelled positron emission tomography (PET) imaging probes is identification of metabolically stable sites to incorporate the <sup>18</sup>F radioisotope. Metabolic loss of <sup>18</sup>F from PET probes <i>in vivo</i> can lead to misleading biodistribution data as displaced <sup>18</sup>F can accumulate in various tissues.In this study we report on <i>in vitro</i> hepatic microsomal metabolism of novel caffeine containing bifunctional compounds (C<sub>8</sub>-6-I, C<sub>8</sub>-6-N, C<sub>8</sub>-6-C<sub>8</sub>) that can prevent <i>in vitro</i> aggregation of α-synuclein, which is associated with the pathophysiology of Parkinson’s disease. The metabolic profile obtained guided us to synthesize stable isotope <sup>19</sup>F-labelled analogues in which the fluorine was introduced at the metabolically stable N7 of the caffeine moiety.An <i>in vitro</i> hepatic microsomal metabolism study of the <sup>19</sup>F-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 <i>in vitro</i> strategy is valuable for avoiding costly stability failures when designing radiolabelled compounds for PET imaging. A challenge in the development of novel <sup>18</sup>F-labelled positron emission tomography (PET) imaging probes is identification of metabolically stable sites to incorporate the <sup>18</sup>F radioisotope. Metabolic loss of <sup>18</sup>F from PET probes <i>in vivo</i> can lead to misleading biodistribution data as displaced <sup>18</sup>F can accumulate in various tissues. In this study we report on <i>in vitro</i> hepatic microsomal metabolism of novel caffeine containing bifunctional compounds (C<sub>8</sub>-6-I, C<sub>8</sub>-6-N, C<sub>8</sub>-6-C<sub>8</sub>) that can prevent <i>in vitro</i> aggregation of α-synuclein, which is associated with the pathophysiology of Parkinson’s disease. The metabolic profile obtained guided us to synthesize stable isotope <sup>19</sup>F-labelled analogues in which the fluorine was introduced at the metabolically stable N7 of the caffeine moiety. An <i>in vitro</i> hepatic microsomal metabolism study of the <sup>19</sup>F-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 <i>in vitro</i> strategy is valuable for avoiding costly stability failures when designing radiolabelled compounds for PET imaging.