Innovative PET Tracer [11C]GW457427: A Preclinical Breakthrough for Neutrophil Elastase Detection and Imaging

Neutrophils, key components of our innate immune system, serve as the initial defense against invading pathogens. However, excessive immune response can lead to severe immuno-inflammatory conditions, causing tissue damage and potentially organ failure. Research has implicated neutrophil elastase (NE) in various human diseases, including inflammatory bowel disease, COPD, AAA, certain cancers, and more recently, COVID-19. The lungs are particularly vulnerable to the destructive effects of NE.

This study introduces the development of a selective PET tracer, 11C-GW457427, designed to serve as a biomarker for NE activity, marking a significant step towards human studies. The tracer was synthesized through a methylation process and underwent rigorous quality control measures, ensuring high purity and specific binding characteristics. In vitro and in vivo tests confirmed its specificity to NE, with elevated uptake observed in a lung inflammation model, correlating strongly with NE content.

The tracer's radiochemical yield was around 45%, with a purity exceeding 98% and a molar activity between 130-360 GBq/μmol. Metabolic studies in rats showed a balance between tracer availability for binding and blood clearance, with substantial amounts of intact tracer present in plasma at key time points. Radioactivity was efficiently cleared from the body, primarily through hepatobiliary excretion, without accumulation in vital organs.

A dosimetry analysis estimated a low whole-body effective dose, suggesting that multiple PET-CT scans could be safely conducted within acceptable radiation exposure limits. The study concludes that 11C-GW457427 is a promising PET biomarker for NE, with a validated production process and no observed toxicity, and is currently under evaluation in a First-In-Man PET study.