In vivo measurement of PDE10A enzyme occupancy by positron emission tomography (PET) following single oral dose administration of PF-02545920 in healthy male subjects

Target Engagement of a Phosphodiesterase 2A Inhibitor Affecting Long-Term Memory in the Rat

“…Receptor/target occupancy has been widely used as a platform to explore target engagement for targets such as G-protein-coupled receptors (Kapur et al, 1995;Hargreaves, 2002;Yokoi et al, 2002;Raddad et al, 2016) and transporters (Martin-Facklam et al, 2013;Finnema et al, 2015) in drug discovery and development. Efforts have been made to demonstrate target occupancy for enzymes (Freedman et al, 2005;Delnomdedieu et al, 2017) as well. For some enzymes, one problem for occupancy studies is the cooperativity of the endogenous substrate with the enzyme itself when the compound investigated is the enzyme inhibitor.…”

Fluid and imaging biomarkers for Huntington's disease

“…Nevertheless PET has the advantage that it may provide more specific information about pathological processes and a potential future role for PET could be as a biomarker for target engagement in smaller proof of concept or phase 1 studies. For example, PET was recently utilised to demonstrate effective target engagement of a novel PDE10A inhibitor following a single dose which supported further clinical development into a phase 2 trial (Delnomdedieu, Forsberg et al 2017). Amyloid PET has found a useful role in Alzheimer's disease in both experimental and clinical use (Laforce, Soucy et al 2018), and a ligand capable of binding some pathogenic form of mutant huntingtin protein could provide a valuable PET biomarker for relevant pathology and regional brain tissue target engagement in huntingtin lowering studies (MacDonald, Borrowsky et al 2015).…”

Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

“…Additionally, this study was aiming to approve the ability of MP-10 to enter the brain after oral administration as well as to estimate appropriate doses for future clinical trials by correlating its serum concentration and the percentage of enzyme occupancy. Application of 10 mg, 20 mg and 30 mg of MP-10 revealed mean MP-10 serum concentrations of about 31 ng/mL, 75 ng/mL and 99 ng/mL within 1.5 h after administration, respectively, indicating a dose-related increase of the systemic exposure to MP-10 [142]. Briefly, a single oral dose of 30 mg of MP-10 revealed adverse side effects in one volunteer, like fatigue, somnolence and musculoskeletal stiffness, and consequently lower doses were applied for further investigations [142].…”

“…Application of 10 mg, 20 mg and 30 mg of MP-10 revealed mean MP-10 serum concentrations of about 31 ng/mL, 75 ng/mL and 99 ng/mL within 1.5 h after administration, respectively, indicating a dose-related increase of the systemic exposure to MP-10 [142]. Briefly, a single oral dose of 30 mg of MP-10 revealed adverse side effects in one volunteer, like fatigue, somnolence and musculoskeletal stiffness, and consequently lower doses were applied for further investigations [142]. Based on the [ 18 F]30 PET scans, PDE10A occupancies in whole striatum, caudate nucleus and putamen of around 21-28% at 10 mg and 52% at 20 mg of MP-10 were estimated consistent with the observed increased systemic exposure of MP-10 at higher doses.…”