Lysosomal binders and radiolabelled substrates as PET ligands for senescence and lysosomal storage diseases
A suite of fluorine-18 radiolabelled PET ligands targeting senescence biomarkers and lysosomal storage disease features, including lipofuscin accumulation, glycogen storage, and beta-galactosidase activity. These probes enable dual-modality fluorescence and PET imaging for research into aging, cancer cell senescence, and lysosomal storage disorders.
Overview
This research programme develops a portfolio of fluorine-18 (18F) radiolabelled PET imaging ligands designed to detect senescence biomarkers and pathological features of lysosomal storage diseases (LSDs). The ligands target key lysosomal alterations including glycogen accumulation, lipofuscin deposition, and beta-galactosidase activity. By exploiting these shared cellular features, the technology aims to provide non-invasive imaging tools for studying disease progression and therapeutic response in aging, oncology, and LSD research.
The approach addresses a critical unmet need: lipofuscin accumulation is a hallmark of multiple LSDs, such as Pompe disease, and is also a marker of cellular senescence. Imaging these biomarkers with PET could accelerate translational research and preclinical drug development across multiple disease areas.
Technical specifications
Lead candidate probes:
- 18F-lipoBinder – a fluorine-18 radiolabelled chalcone small molecule based on the CDg4 scaffold that binds stored glycogen, enabling dual-modality fluorescence and PET imaging
- 18F-NFTG – 18F-N-(methyl-(2-fluoroethyl)-1H-[1,2,3]triazole-4-yl)glucosamine for imaging glycogenesis during quiescence
- 18F-b-Gal – a beta-galactosidase activity probe with improved sensitivity compared to the existing 18F-FPyGal
Validation work completed:
- In vitro testing in T47D and MCF-7 breast cancer cell lines treated with palbociclib and MLN8054 confirmed correlation between 18F-lipoBinder uptake, lipofuscin autofluorescence, and beta-galactosidase staining
- 60-minute dynamic PET imaging in mice demonstrated favourable pharmacokinetics and metabolic profile, with analysis of plasma, liver, and urine by radio-HPLC
- Lead chemistry selected based on retention of desired pharmacophore and efficient radiolabelling
Planned future validation:
- Imaging young (3-month) and old (22-month) p16-3MR transgenic mice versus wild-type controls, with senescent cell clearance via ganciclovir treatment (2-year study)
- T47D-p16LUC tumour model in immunocompromised mice to assess senescence induction and imaging by luminescence and PET (9-month study)
Technology readiness level
The technology is at an advanced preclinical stage. Lead compounds have been synthesised, radiolabelled, and characterised in vitro with supporting in vivo PET imaging and metabolite analysis in mouse models demonstrating favourable pharmacokinetics. Future validation plans involve transgenic and tumour-bearing mouse models to confirm specificity for senescence and LSD-associated biomarkers. The programme is seeking partnership and funding for key personnel, consumables, animals, and imaging costs to advance these studies.
About Imperial College London
Imperial College London is a STEM‑focused public research university with a large postgraduate community and an entrepreneurial culture. Industry engages through the White City innovation district, where the university offers incubator and scale‑up labs, wet‑lab and prototyping facilities, co‑location with corporate R&D and startups, and a dedicated technology transfer office. Integration with a major NHS hospital system provides access to clinical cohorts, trials infrastructure, and translational expertise, while corporate relations streamline sponsored research and consortia. Research is supported by competitive funding from UK Research and Innovation councils, the National Institute for Health and Care Research, European programs, and major foundations.
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