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

The Bifunctional Dimer Caffeine-Indan Attenuates α-Synuclein Misfolding, Neurodegeneration and Behavioural Deficits After Chronic Stimulation of Adenosine A1 Receptors

“…To further investigate the pharmacokinetics of 18 F-C8-6-I and its metabolic stability in vivo, a metabolic stability study was carried out via radio HPLC analysis on extracts of liver, pancreas, and brain at 40 min p.i. Previous knowledge of the in vitro metabolic stability profiles of 19 F-C8-6-I and C8-6-I in human, mouse and rat liver microsomes [11] suggested that a significant percentage of the parent 19 F-C8-6-I remained after 1 h incubation, which may allow in vivo radio metabolite analysis of 19 F-C8-6-I in various tissues including the brain, liver and GI tract. However, the in vivo metabolic stability of 18 F-C8-6-I has not been analyzed.…”

“…However, it was argued that linking these compounds and other similar neuroprotective drugs in dimers or trimers would decrease the misfolding and aggregation of α-Syn without risking the safety of the patients [10]. These compounds can be also referred to as bifunctional drugs [11]. They are connected via a six-carbon alkyl linker to minimize solubility issues and retain the flexibility that will allow further binding to α-Syn.…”

“…To test the blood-brain barrier permeability and distribution of the dimer we also performed an in vivo study with CD-11 albino mice using PET imaging. Before PET imaging, the dimer was radiolabeled with fluoride-18 [ 18 F] radioisotope [11]. Therefore, PET imaging allows the quantitation of drug concentration, distribution, and pharmacokinetics of radiotracers [15], as well as providing information about physiology such as metabolism, receptor concentration, and transport across cell membranes [16,17], as a result, PET is a useful tool in drug development [18][19][20].…”

“…PET can be used to non-invasively infer molecule distribution in vivo and brain exposure [17,21]. Recent advances in radiochemistry now mean many drug molecules can be rapidly labelled with radionuclides such as 11 C or 18 F and used for biodistribution studies [22,23]. Radiotracers are commonly used in non-clinical studies to assess the drug absorption, distribution, metabolism and excretion (ADME) profile of a drug [24].…”

Diagnostic and therapeutic agents that target alpha-synuclein in Parkinson’s disease

“…To achieve this goal, preclinical studies such as metabolism was conducted, and metabolic studies of these compounds provided useful information about their in vitro lifetime as well as the most appropriate position to include a signal moiety on the bifunctional compounds. Nwabufo et al, developed an appropriate analytical method for the qualitative and quantitative analysis of these novel bifunctional compounds [ 148 ] and in vitro phase 1 metabolism of these compounds in mouse, rat and human liver microsomes showed that C 8 -6-N undergoes rapid metabolism, C 8 -6-I undergoes moderate metabolism, and C 8 -6-C 8 remained intact after 60 min incubation time [ 149 , 150 ].…”