Characterization of a novel sigma-2 receptor PET probe for brain imaging studies

Objectives: Sigma-2 receptor (S2R) antagonists have been reported to antagonize beta amyloid (Abeta) oligomer trafficking to neurons, thereby having a disease-modifying benefit for Alzheimer’s disease (AD) patients. Consequently, a PET radiotracer for studying the role of the S2R in AD is needed. Unfortunately, [18F]ISO-1, the only S2R-selective PET probe approved for human use, has low brain uptake. The goal of this study was to develop a S2R-selective PET probe for brain imaging studies. Accordingly, we report the in vitro and in vivo evaluation of [11C]PX-II-116, a novel S2R-selective PET radiotracer for brain imaging studies. Materials Competition studies of nonradioactive PX-II-116 (0.01 - 300 nM) were conducted at both S2R ([3H]DTG and [125I]RHM-4) and sigma-1 receptors (S1R; [3H](+)-pentazocine) for calculation of inhibition constants (Ki). For the in vivo biodistribution studies, male Balb/c mice (N = 3) were used and each one was given a dose of 0.2-0.5 mCi [11C]PX-II-116. Animals were sacrificed at 1 hour and the results were calculated as percentage of injected dose per gram of organ weight (%ID/g). To verify tracer specificity to S2R, another three male Balb/c mice were given a dose of 0.2-0.5 mCi [11C]PX-II-116 co-injected with 0.6 mg/kg of unlabeled PX-II-116. Animals were sacrificed at 1 hour and brain and muscle samples were dissected to calculate the brain-to-muscle ratio. To further explore the brain distribution of [11C]PX-II-116, PET imaging study in rhesus macaque was conducted (3.6 mCi, 90-min dynamic scan). Tracer uptake of the brain images were represented as standardized uptake values (SUV). Results [11C]PX-II-116 presents subnanomolar S2R affinity (Ki = 0.52 ± 0.32nM with [3H]DTG and Ki = 0.06 ± 0.01nM with [125I]RHM-4) and low affinity for S1R (768 ± 22 nM). For the biodistribution study, the tracer showed a high brain uptake (8.35 ±1.09 %ID/g) 1 hour after i.v. injection of the tracer. The blocking group showed a 3- to 4-fold lower brain-to-muscle ratio compared to the control group. PET study in rhesus monkey clearly demonstrated that the tracer can penetrate the blood-brain-barrier (BBB) with brain uptake reaching a maximum at 10 min after tracer injection in the cortex, thalamus, and striatum, followed by a slow rate of wash out. Conclusions [11C]PX-II-116 not only has high affinity and selectivity for S2R vs. S1R, but also has a high brain uptake in both rodent and nonhuman primate PET imaging studies. Our results suggest th