Abstract
P655
Introduction: The sigma-2 receptor (σ2R) is a subtype of sigma receptors and recently identified as transmembrane protein 97 (TMEM97).1 It has emerged as an attractive therapeutic target for cancers and neurologic disorders such as Alzheimer’s disease.1 So far, development of σ2R radiotracers has been focused primarily on tumor imaging and currently available tracers have limited brain uptake which restricts their applications in neuroimaging. Brain penetrant, σ2R-selective PET radiotracers would be significant additions to neurological research. We previously reported [18F]SYB4 as a novel, brain-penetrant tracer for imaging σ2R in rodents2 and non-human primates3. The objective of the present study is to evaluate an analogous radioligand, [18F]SYB6, in monkeys and compare the performance of these two tracers.
Methods: Radiosynthesis of the radiotracer 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-6-(2-18F-fluoroethoxy)-1H-indole ([18F]SYB6) was accomplished via 18F-fluorination of its tosylate precursor. PET imaging in rhesus monkeys was carried out on the Focus 220 scanner. Arterial blood samples were collected for metabolite analysis and measurement of the parent input function. Binding specificity was assessed by blocking studies with the σ2R selective antagonist CM398. Brain time-activity curves (TACs) were analyzed with quantitative kinetic modeling approaches to estimate regional volume of distribution (VT). Target occupancy across the brain and non-displaceable volume of distribution (VND) were then determined from the occupancy plot. Regional specific binding signals were determined as non-displaceable binding potential (BPND) using baseline VT values and VND from the blocking scans.
Results: [18F]SYB6 was synthesized in 50 min with > 99% radiochemical purity. Mean parent fraction in plasma was 51% at 30 min after injection of [18F]SYB6, compared with ~36% for [18F]SYB4. Blocking drug appeared to increase the rate of tracer metabolism, with parent fraction of 37% at 30 min in the pre-treatment scans. In the brain, [18F]SYB6 exhibited fast and reversible kinetics with peak SUV of 2.5 – 3.6 within 30 min in grey matter regions (SUV of 2.2 – 4.5 for [18F]SYB4). Regional distribution was similar between [18F]SYB4 and [18F]SYB6 and consistent with the expression of σ2R in the brain: high in the cerebellum and putamen, followed by hippocampus, thalamus, caudate and amygdala, and lowest in centrum semiovale (white matter). Regional TACs were well fitted with both the 1-tissue compartment model (1TCM) and multilinear analysis method-1 (MA1) to derive reliable VT estimates, ranging from 14.9 mL/cm3 in amygdala to 24.1 mL/cm3 in cerebellum. In the blocking scans of [18F]SYB6 with CM398 (0.2 mg/kg), reduced tracer uptake and VT were observed across all brain regions. Target occupancy was 68%, with VND of 7.8 mL/cm3. Regional BPND values ranged from 0.92 in amygdala to 2.11 in cerebellum for [18F]SYB6, similar to those from [18F]SYB4: 0.56 – 2.59.
Conclusions: Evaluation of the novel radiotracer [18F]SYB6 demonstrated that it readily enters the brain and binds to σ2R in nonhuman primates with fast tissue kinetics and specific binding signals similar to those of [18F]SYB4. We now have two brain penetrant PET radiotracers to image and quantitate σ2R in the brain.
References: [1] Alon et al. Proc Natl Acad Sci USA. 2017; 114:7160-7165 [2] Zhang et al. Acta Pharmaceutic Sinica B 2022; 12 (3):1406 – 1415 [3] Alluri et al. Journal of Nuclear Medicine June 2022; 63 (supplement 2):2845
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