Synthesis and Preclinical Characterization of a Cationic Iodinated Imaging Contrast Agent (CA4+) and Its Use for Quantitative Computed Tomography of Ex Vivo Human Hip Cartilage

Contrast agents that go beyond qualitative visualization and enable
quantitative assessments of functional tissue performance represent
the next generation of clinically useful imaging tools. An optimized
and efficient large-scale synthesis of a cationic iodinated contrast
agent (CA4+) is described for imaging articular cartilage. Contrast-enhanced
CT (CECT) using CA4+ reveals significantly greater agent uptake of
CA4+ in articular cartilage compared to that of similar anionic or
nonionic agents, and CA4+ uptake follows Donnan equilibrium theory.
The CA4+ CECT attenuation obtained from imaging ex vivo human hip
cartilage correlates with the glycosaminoglycan content, equilibrium
modulus, and coefficient of friction, which are key indicators of
cartilage functional performance and osteoarthritis stage. Finally,
preliminary toxicity studies in a rat model show no adverse events,
and a pharmacokinetics study documents a peak plasma concentration
30 min after dosing, with the agent no longer present in vivo at 96
h via excretion in the urine.