Small molecule PET ligands targeting lysosomal proteins for diagnostic imaging

Overview

This research program focuses on developing small molecule binders of lysosomal proteins as candidate PET (positron emission tomography) imaging ligands. The compounds target key enzymes involved in mucopolysaccharidoses (MPS), a group of lysosomal storage disorders, including IDS, IDUA, SGSH, and NAGLU. These enzymes are responsible for degrading heparan sulfate, and their dysfunction leads to disease. The small molecule inhibitors have been designed as pharmacological chaperones—molecules that bind to and stabilize misfolded enzymes—and several candidates already contain a fluorine atom or can be readily derivatized with fluorine or other functional groups suitable for PET imaging.

The value proposition lies in addressing the unmet need for diagnostic imaging agents for lysosomal storage diseases. PET ligands derived from these chaperone scaffolds could enable non-invasive visualization of enzyme distribution, disease progression, and treatment response. The research is positioned at the intersection of rare disease diagnostics and molecular imaging, offering potential applications in both clinical diagnostics and preclinical drug development.

Technical specifications

Target enzymes and compounds:

• Inhibitors designed against IDS, IDUA, SGSH, and NAGLU—lysosomal enzymes that degrade heparan sulfate
• Compounds validated using mutant fibroblast cell lines for MPS I, II, IIIA, and IIIB
• Chaperone activity confirmed through increased lysosomal enzyme activity and decreased cellular heparan sulfate levels, quantified by LC-MS/MS

Structural and computational approaches:

• X-ray crystallographic studies underway with leading compounds bound to SGSH and NAGLU
• Molecular modelling to inform compound optimization
• Virtual screening programs in place for NAGLU and SGSH, with planned extension to IDS and IDUA

PET ligand development pathway:

• Several compounds already contain fluorine or can be derivatized with fluorine or PET-compatible functional groups
• Next steps involve incorporating PET-suitable functionality while preserving binding affinity
• Retesting planned to confirm that derivatization does not compromise enzyme affinity

Technology readiness level

The program is at an advanced preclinical stage. Multiple compounds have been synthesized and validated in cell-based assays, with several showing chaperone activity and reduced heparan sulfate accumulation. Lead compounds are ready for evaluation in mouse models of disease. Structural biology work (X-ray crystallography) and computational screening are actively informing lead optimization. The next phase requires synthesis of improved analogs, incorporation of PET-compatible functionality, and preclinical evaluation—including animal model studies—to advance toward clinical translation. The research group is seeking partnership to support PET development, testing, and funding for personnel and consumables.