Fluselenamyl: Evaluation of radiation dosimetry in mice and pharmacokinetics in brains of non-human primate

Abstract

IntroductionTo allow quantitative assessment of therapeutic efficacy for therapeutic interventions (either approved or undergoing FDA approvals) for either inhibiting or reducing development of Aβ pathophysiology in vivo, 18F-labelled tracers, such as Florbetapir, Florbetaben, and Flutemetamol have been approved. Previously, we have reported on development and preclinical validation of 18F-Fluselenamyl, comprising traits of translatable Aβ imaging agents. Herein, we report the dosimetry data for 18F-Fluselenamyl to provide radiation dose deposited within organs and determine effective dose (ED) for human studies, while also evaluating its pharmacokinetics in the nonhuman primate brains. MethodsTo evaluate safety profiles of 18F-Fluselenamyl for enabling its deployment as a PET imaging agent for monitoring Aβ pathophysiology in vivo, we estimated the human radiation dosimetry extrapolated from rodent biodistribution data obtained by standard method of organ dissection. Animal biodistribution studies were performed in FVB/NCR mice (20 males, 20 females), following tail-vein injection of the tracer. Following euthanasia of mice, organs were harvested, counted, radiation dose to each organ and whole body was determined using the standard MIRD methodology. For evaluation of pharmacokinetics in non-human primates, following intravenous injection of the tracer, dynamic PET scan of rhesus monkey brains were performed, and co-registered with MR for anatomical reference. Parametric images of tracer transport rate constant and distribution volume relative to cerebellum were generated using a simplified reference tissue model and a spatially-constraint linear regression algorithm. ResultsThe critical organ in humans has been determined to be the gall bladder with a gender average radiation absorbed dose of 0.079 mGy/MBq with an effective dose of 0.017 mSv/MBq and 0.020 mSv/MBq, in males and females, respectively. Therefore, these data provide preliminary projections on human dosimetry derived from rodent estimates, thereby defining safe imaging conditions for further validations in human subjects. Additionally, the tracer penetrated the non-human primate brain and excreted to background levels at later-time points thus pointing to the potential for high signal/noise ratios during noninvasive imaging. Tissue time activity curves (TACs) also show fast initial uptake with maximum projection of activity at 2–6 min post administration followed by clearance of activity at later time-points from cortex, cerebellum, and white matter of nonhuman primate brain. Parametric images confirmed that the 18F-Fluselenamyl has relative high transport rate constant at striatum, thalamus, and cortex. ConclusionsThe data obtained from radiation dosimetry studies in mice indicate that 18F-Fluselenamyl can be safely used for further evaluation in humans. Additionally, 18F-Fluselenamyl demonstrated ability to traverse the blood brain barrier (BBB) and indicated high initial influx, followed by clearance to background levels in non-human primate brains. Combined information indicates that 18F-Fluselenamyl would be a potential candidate for detecting amyloid plaques in the living human brain.