Abstract
241594
Introduction: The sigma-2 receptor (σ2R) is one of the two subtypes of σR and has emerged as a potential therapeutic target for neurological disorders. Quantitative PET imaging of σ2R in the brain will help with the investigation of σ2R involvement in diseases and their treatment.1 Previously reported σ2R radiotracers have been shown to be unsuitable for neuroimaging owing to their low and/or non-specific brain uptake. We have been engaged in the development of brain penetrant σ2R ligands and recently discovered three radiotracers ([18F]SYB4, [18F]SYB5, and [18F]SYB6) with promising binding and imaging properties in rodent studies.2 Herein we report the quantitative evaluation of these novel tracers in non-human primates.
Methods: PET scans were performed in four rhesus monkeys on the Focus 220 scanner with arterial blood sampling during the scans to analyze for parent tracer and radioactive metabolites and determination of the parent input function in plasma. Blocking experiments were performed using the σ2R and σ1R selective antagonists CM398 and FTC-146, respectively, to assess binding specificity and selectivity. The one-tissue compartment (1TC) model and multilinear analysis-1 (MA1) method were employed for kinetic analysis of the imaging data to estimate regional volume of distribution (VT). Target occupancy by blocking drugs and non-displaceable volume of distribution (VND) were determined from the occupancy plots. Non-displaceable binding potential (BPND) was then calculated from baseline VT and blocking VND values to gauge the magnitude of specific binding for each tracer.
Results: In baseline scans, all three tracers showed relatively fast decrease of parent fraction in plasma (~40% at 30 min after tracer injection), which became even faster in blocking studies (~25% at 30 min). Uptake of all three tracers in monkey brain was high, and with fast and reversible kinetics in grey matter regions. Peak SUV was 2.2 – 4.5 for [18F]SYB4, 2.4 – 4.1 for [18F]SYB5, and 2.5 – 5.6 for [18F]SYB6 within 30 min post injection. Distribution of both [18F]SYB4 and [18F]SYB6 was heterogeneous across brain regions and similar: high in the cerebellum, followed by putamen, hippocampus, thalamus, and low in the centrum semiovale (white matter), while that of [18F]SYB5 was more homogenous. Brain regional time-activity curves (TACs) were well-fitted by both the MA1 and 1TC models, and mean MA1 VT (mL/cm3) values were calculated as 14 (amygdala) – 23 (cerebellum) for [18F]SYB4 (n = 3), 12 (caudate/putamen) – 16 (cerebellum) for [18F]SYB5 (n = 1) and 15 (amygdala) – 23 (cerebellum) for [18F]SYB6 (n = 3). In blocking studies, the σ2R selective antagonist CM398 greatly reduced the uptake and VT values of [18F]SYB4 and [18F]SYB6 across all brain regions, and to a much less degree those of [18F]SYB5, while the σ1R-selective antagonist FTC-146 induced negligible changes in the uptake and VT values of [18F]SYB4. As a measure of specific binding signals, regional BPND values were high for both [18F]SYB4 (range: 0.9 – 2.1) and [18F]SYB6 (range: 1.2 – 2.5), and lower for [18F]SYB5 (range: 0.05 – 0.4). These results are consistent with those from previous studies in rodents.2
Conclusions: Conclusion: Quantitative evaluation of three novel σ2R radiotracers in rhesus monkeys demonstrated that both [18F]SYB4 and [18F]SYB6 readily enters the brain with good uptake, fast kinetics, and high levels of specific binding signals in vivo. [18F]SYB5 also displays good brain uptake, albeit with lower level of specific binding. Taken together, we have found two radiotracers with promising characteristics for PET imaging of σ2R in the brain. Their translation to studies in humans will help elucidate this receptor’s involvement in diseases and therapeutic development.
References:
• Nicholas et al. Alz Dement 2021; 17:1365
• Zhang et al. Acta Pharm Sinica B 2022; 12:1406
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.