Development of a cationic contrast agent for targeted imaging of glycosaminoglyca

DESCRIPTION (provided by applicant): There is no known cure for Osteoarthritis (OA), a debilitating disease that afflicts 27 million people and costs 125 billion, annually. In OA, the articular cartilage is degraded and it has a limited capacity to self-heal; therefore, rendering a diagnosis at a late stage is ineffective at preventing further cartilage degeneration. Currently, there are no contrast agents that are specifically designed for quantitative CT imaging of glycosaminoglycan (GAG) content in articular cartilage. Ionic Pharmaceuticals is developing a novel cationic CT contrast agent for targeted quantitative imaging of changes in GAG content and morphology of articular cartilage. Recent data demonstrates that the cationic contrast agent (CA4+) is five times more sensitive at imaging ex vivo and in vivo articular cartilage than currently available commercial anionic contrast agents. This superior performance of the cationic contrast agent is attributed to the electrostatic attraction between the cationic contrast agent and the negatively-charged GAGs present in articular cartilage. Two critical steps towards commercialization of this technology and the use of this contrast agent in the clinic are addressed in this proposal: 1) synthetic scale- up, analytical and formulation development; and 2) pharmacokinetics. Thus, the specific aims of this proposal are: Aim 1: Larger scale (~200 g) synthesis of CA4+, development of analytical methods, and formulations for future pre-clinical safety, toxicology, andpharmacokinetic studies. Aim 2: Synthesis of the C14 labeled contrast agent and pharmacokinetics of C14- CA4+ (plasma-time course, routes and rates of excretion and tissue distribution) after IV and intra-articular dose in rats. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Sensitive imaging technologies for monitoring changes in osteoarthritic cartilage are urgently needed. Currently, there is no known cure or a sensitive imaging method that can be used to diagnose osteoarthritis at an earlystage. This SBIR Phase I proposal furthers the development of a new cationic CT contrast agent for quantitative imaging of cartilage, by manufacturing it on a large scale and determining its pharmacokinetics.