Lysosomal binders and radiolabelled substrates as PET ligands for senescence and lysosomal storage diseases

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.