Comparison of partial least-square method and canonical correlation analysis in a quantitative structure-retention relationship study

OBJECTIVES: Either venous or arterial thrombosis is a potentially life-threatening event and existing diagnostic modalities are inadequate to diagnose and to determine the morphology of the evolving thrombus. Thus development of a noninvasive imaging agent that can detect clot location remains a critical and unmet need in nuclear diagnostic medicine. The present study was undertaken to determine the potential of platelet GPIIb/IIIa receptors compared with direct thrombin inhibitors, in the detection of venous and arterial clots. METHODS: Initially, the validity of exploiting the degree and extent of specific uptake and retention of a potent GPIIb/IIIa receptor antagonist in venous and in arterial thrombus was confirmed in vitro in artificially created arterial- or venous-type clots, using the radiolabeled antagonist, 3H-DMP728. This was followed by comparing the in-vivo clot/blood distribution of various technetium-99m (99mTc)-labeled, DMP728-derived, GPIIb/IIIa receptor antagonists and of thrombin inhibitors, over time, in mixed arterial/venous or venous clots in arteriovenous shunt and in venous clot models in dogs. In addition, we performed noninvasive single-photon emission tomographic imaging of the venous clot in a deep vein thrombosis model in dogs. RESULTS: Our data confirmed that potency for the platelet GPIIb/IIIa receptors was maintained after radiolabeling of the parent active GPIIb/IIIa receptor antagonists. DMP728 demonstrated a relatively greater affinity for activated than for unactivated human platelets, which might be essential for attaining an optimal thrombus/blood (target/background) distribution ratio and the optimal detection of small clots (i.e. greater sensitivity). CONCLUSIONS: These data suggest a potential utility of 99mTc-GPIIb/IIIa receptor antagonists, but not of direct thrombin inhibitors, in the diagnosis of venous clots in deep vein thrombosis, pulmonary embolism and arterial thromboembolic disorders including stroke and coronary and peripheral artery thrombotic disorders.