Development of novel imaging agents for the prospective quantification of joint damage to reduce animal numbers in osteoarthritis research

Preclinical models of osteoarthritis (OA) are widely used for target discovery and drug development. The inability to visualise cartilage sensitively, non-invasively and prospectively is hampering their use and significantly impacting on the numbers of animals used for such studies. Semi-quantitative assessment by histological analysis of the joint post-mortem is the current gold standard, but requires mice to be killed at several time points during the study. The development of a non-invasive imaging method that would be able to visualise the loss of articular cartilage in vivo would greatly reduce the numbers of animals used by being able to follow disease in a single animal. Furthermore, a truly quantitative assessment would improve accuracy and reproducibility, leading to reduction of numbers required to power studies. Whilst ex vivo methodologies have demonstrated that it is possible to develop agents with cartilage specificity, none of these are suitable for in vivo use.

The new imaging agents we will develop are based on a small library of chemical compounds we originally developed to increase the retention of potential drugs in joints. Preliminary work shows that these compounds (fluorescently tagged) bind specifically to cartilage following intra articular injection. We will modify this library of compounds to allow visualisation by CT to obtain non-invasive measures of cartilage volume. This will be achieved by incorporation of multiple iodines into the compounds to create CT-contrast agents.

This project grant will fund the development of these new CT-contrast agents including their synthesis, in vitro validation, toxicity, and prospective utility in a surgical model of OA. The successful imaging of articular cartilage and quantification of tissue damage during the course of OA will significantly and rapidly reduce the number of animals required in preclinical OA studies.