High-throughput miniaturized chemistry and label-free screening platform for lysosomal binder discovery and accelerated PET tracer development

Overview

This solution combines an automated, miniaturized high-throughput chemistry and label-free screening platform with a cassette dosing PET imaging strategy to accelerate the discovery of small molecule binders against lysosomal proteins and glycosaminoglycans. The goal is to identify brain-penetrant candidate radiotracers for positron emission tomography (PET), addressing a bottleneck in CNS drug discovery and diagnostic imaging.

The platform addresses two major challenges in early-stage radiopharmaceutical development: identifying high-quality binders against difficult targets and rapidly evaluating blood-brain barrier penetration. By integrating synthesis, screening, radiolabeling, and in vivo imaging into a streamlined workflow, the approach aims to shorten the timeline from library design to validated PET candidate.

Technical specifications

Core capabilities:

• Automated miniaturized synthesis using the AMADEUS platform for nanoliter-scale chemistry
• Label-free high-throughput screening via native protein mass spectrometry or surface plasmon resonance (SPR)
• One-well, one-compound library synthesis with MS-triggered UPLC purification
• Incorporation of PET-compatible precursor functional groups (e.g., boronic acid) into hit expansion libraries
• 18F and 11C radiolabeling of small mixture libraries of approximately 10 compounds
• Cassette dosing in mice for simultaneous biodistribution assessment
• Deconvolution and singleton validation of compounds showing target organ uptake

Validated chemistry scope:

• Boronic acids, indoles, iminopyrrolidines, and isoquinolines
• Covalent 3CLpro inhibitor discovery via high-throughput crystallography
• Antagonists of protein-protein interactions (menin-MLL)

Technology readiness level

The AMADEUS synthesis and screening platform has been published and validated across multiple compound classes and target discovery campaigns. The radiolabeling and in vivo pharmacodynamic evaluation methodology has also been previously published. The specific combination of miniaturized library synthesis for lysosomal targets followed by mixture labeling and cassette-dose PET imaging is presented as an unprecedented, novel extension of the validated platform. The project is positioned for initial target selection, library design, and pilot cassette dosing studies.