Lung muscarinic receptor occupancy by tiotropium: translational PET studies in non-human primates and humans

Abstract BackgroundThe aim of the present translational PET study was to estimate occupancy of tiotropium at muscarinic acetylcholine receptors (mAChR) in the lungs in vivo. The relationship between the tiotropium exposure and receptor occupancy (RO) in the lung was assessed in non-human primates (NHPs) after intravenous injection of tiotropium doses at a broad dose interval (0.1-1mg/kg). The feasibility of measuring mAChR occupancy in the human lung was then confirmed in seven healthy human subjects after inhalation of a single therapeutic dose of tiotropium (18mg). PET examinations were performed using radioligand [11C]VC-002. Occupancy in lungs was estimated using Lassen plot analysis of parametric images showing total radioligand binding (total distribution volume, VT).ResultsThere was an evident effect of tiotropium on [11C]VC-002 binding to mAChRs in lungs in both NHPs and humans. In NHPs, the occupancy was 11 to 78%, increasing in a dose dependent manner. The Lassen-plot based estimate of non-displaceable binding in NHPs was about 10% of the VT. In humans, occupancy was 6-65%, and non-displaceable binding (VND) was about 20% of total binding, VT at baseline. ConclusionsThe results demonstrated that [11C]VC-002 binds specifically to mAChRs in the lungs such that it allows for the detection and quantification of lung muscarinic receptor occupancy following administration of an intravenously administered or inhaled muscarinic antagonist drugs. The methodology has potential for dose finding and comparison of drug formulations in future applied studies. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT03097380, registered: 31 March 2017, url: https://clinicaltrials.gov/ct2/show/NCT03097380