11C-UCB-J is a positron emission tomography (PET) radioligand that has been used in humans for synaptic vesicle glycoprotein 2A (SV2A) imaging and as a potential synaptic density marker. The centrum semiovale (CS) is a proposed reference region for noninvasive quantification of 11C-UCB-J, due to negligible concentrations of SV2A in this region in baboon brain assessed by in vitro methods. However, in displacement scans with SV2A-specific drug levetiracetam in humans, a decrease in 11C-UCB-J concentration was observed in the CS, consistent with some degree of specific binding. The current study aims to validate the CS as a reference region by (1) optimizing CS region of interest (ROI) to minimize spill-in from gray matter with high radioactivity concentrations; (2) investigating convergence of CS ROI values using ordered subset expectation maximization (OS-EM) reconstruction, and (3) comparing baseline CS volume of distribution ( VT) to nondisplaceable uptake in gray matter, VND. Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CS VT and VND. However, even with these corrections, CS VT overestimated VND by ∼35–40%. These measures showed significant correlation, suggesting that, though biased, the CS may be a useful estimate of nondisplaceable uptake, allowing for noninvasive quantification for SV2A PET.
In this phase I, single‐center, open‐label study of ten heathy adults (18‐45 years; NCT02647697), the PK, safety, and tolerability profile of radiprodil oral suspension in healthy adults were assessed, as well as two PK microsampling techniques. All participants received a single 30 mg radiprodil dose (12 mL oral suspension). Blood was collected at various time points using conventional venous sampling (intravenous catheter or venepuncture), and Mitra™ and Aqua‐Cap™ Drummond microsampling (finger‐prick and blood taken from venous blood sample tubes). Geometric mean radiprodil plasma concentrations from conventional venous samples were above the lower limit of quantification up to 48 hours after administration of a single oral dose of radiprodil. Geometric mean AUC
inf and C
max were 2042 h ng mL
−1 and 89.4 ng mL
−1, respectively. Geometric mean t
½ was 15.8 hour; median t
max was 4 hour (range: 3‐6 hour). Radiprodil exposure variables for Aqua‐Cap™ Drummond sampling were similar to the conventional venous‐derived data. Conversely, radiprodil exposure variables were lower with Mitra™ sampling compared with conventional venous sampling. The geometric mean ratio (90% confidence interval) for C
max of conventional venous versus Mitra™ and Aqua‐Cap™ Drummond sampling (finger‐prick blood) was 0.89 (0.85, 0.94) and 1.03 (0.97,1.08), respectively, and therefore within the conventional bioequivalence range (0.80‐1.25). Radiprodil oral suspension had an acceptable safety, tolerability, and palatability profile. The PK profile of radiprodil oral suspension was established in healthy adults, and was comparable when analyzed using conventional versus microsampling techniques. These results will support future radiprodil paediatric studies.
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