PET radioligands for imaging S1PR5 in CNS disorders
Novel positron emission tomography (PET) radiotracers targeting sphingosine-1-phosphate receptor 5 (S1PR5) for non-invasive investigation of CNS and autoimmune disorders. Leverages highly selective S1PR5 agonist compounds (<10 nM IC50) with radiosynthesis optimization for F-18 or C-11 labeling, enabling preclinical and clinical imaging of brain targets linked to Huntington's, Alzheimer's, Parkinson's, and multiple sclerosis.
Overview
This program develops selective PET radioligands for imaging sphingosine-1-phosphate receptor 5 (S1PR5), a receptor predominantly expressed in the central nervous system (CNS) endothelium and mature oligodendrocytes. S1PR5 plays a critical role in blood-brain barrier (BBB) homeostasis, oligodendrocyte survival, and neuroinflammation regulation, making it a compelling target for investigating CNS disorders such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Currently, tools to study S1PR5 function in living systems are limited, and a validated PET tracer would enable non-invasive target engagement studies, disease mechanism research, and therapeutic monitoring.
Technical specifications
Core compound library:
- Multiple selective S1PR5 agonist scaffolds with IC50 < 10 nM against S1PR5 and > 500 nM selectivity over S1PR1-4
- Lead candidates TZ85110 and TZ85105 identified for radiosynthesis optimization
- Structural modifications introducing methoxy, fluoroethoxy, or fluorine moieties onto aromatic rings to enable C-11 or F-18 labeling
Target tracer profile:
- High brain uptake with reversible pharmacokinetics (brain uptake ratio at 2 min vs. 60 min > 2.5)
- Specific binding showing > 10% difference between diseased and control animals
- No radioactive metabolites crossing the BBB that would interfere with PET signal quantification
- Stable and reproducible kinetic modeling validated in non-human primates
Validation pipeline:
- In vitro binding assays to confirm affinity and selectivity
- PET imaging in HD mouse models to assess disease-related binding
- Monkey PET studies for BBB penetration, metabolite analysis, brain uptake/washout kinetics, and specific binding quantification
- Test-retest reproducibility, dosimetry, and toxicity studies to support exploratory IND (e-IND) filing
Technology readiness level
The program is at an early-to-mid preclinical stage. Lead compounds have demonstrated potent and selective in vitro binding profiles. Radiosynthesis for C-11 and F-18 labeling is in progress, with planned in vivo PET evaluation in rodent disease models and non-human primates. Future steps include selecting an optimal radiotracer candidate and conducting regulatory-enabling studies (test-retest, dosimetry, toxicity) toward an exploratory IND submission. The technology is positioned for translational research partnerships and co-development toward first-in-human imaging studies.
About Washington University in St. Louis
Washington University in St. Louis is a private research university with a large graduate and professional footprint and a major clinical enterprise. Its medical campus is integrated with a leading hospital system, enabling joint clinical research, secure data access, and large-scale trial recruitment. An adjacent innovation district and partner incubators provide flexible lab space, prototyping resources, and corporate co-location, while shared core facilities welcome external users under service agreements. Research is supported by NIH, NSF, DOE, and other competitive federal funding alongside industry sponsorship. A dedicated technology transfer office manages IP, licensing, startup formation, and streamlined sponsored research and clinical trial agreements.
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