Development of new albumin‑binding radiotracers for PET imaging of CSF

The glymphatic system is a brain-wide waste clearance pathway facilitated by CSF flow. Despite its importance, few tools can visualize and quantify its function in vivo without being invasive. The development of novel imaging approaches could bridge this gap and reveal the glymphatic system in action.
This study investigated whether PET imaging of CSF flow could be enabled by radiotracers that bind to albumin – a dominant protein in CSF – to act as a macromolecular carrier and provide quantitative information on the CSF fluid dynamics.
Experiment: Three gallium-68 labelled endogenous albumin tracers and an in vitro labeled fluorine-18 reference tracer based on rat-serum albumin (Al[18F]F-RESCA-RSA) were developed and investigated in rats. Each radiotracer was administered via the lateral tail vein (for static PET/CT studies) or intrathecally through cisterna magna and lumbar cannulations (for dynamic PET/CT studies).
A 15-minute static PET/CT scan was performed using the β-CUBE (PET) and X-CUBE (CT) systems after 15 and 120 minutes of intravenous tracer injection. PET imaging allowed for real-time, quantitative assessment of tracer distribution across CSF pathways, while CT provided anatomical reference for co-registration.
Dynamic PET/CT scans were acquired over 120 minutes and reconstructed to 24×5 minute frames. Standardized uptake values (SUVs) and time-activity curves (TACs) were analyzed in key brain regions (e.g., cortex, hippocampus, striatum) and CSF spaces (e.g., spinal canal, intracranial space).
Results: PET/CT imaging revealed that all tracers entered the intracranial space and spinal canal following infusion. Distribution patterns varied depending on tracer properties.
The fluorine-18-labeled reference tracer (Al[18F]F-RESCA-RSA) showed faster and broader distribution across CSF pathways, including visualization of cervical lymph nodes.
In contrast, gallium-68 tracers showed incomplete albumin binding in vivo, leading to some free tracer dispersing in the rat CSF and interactions with brain tissue based on physicochemical properties rather than albumin transport.
These results highlight Al[18F]F-RESCA-RSA tracer as a strong candidate for future PET-based studies of glymphatic fluid dynamics.
Citation: EJNMMI Radiopharm Chem. 2025 Jul 6;10:38. doi: 10.1186/s41181-025-00365-4
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