Abstract 1914: BMS753951: A Novel Low Molecular Weight Magnetic Resonance Contrast Agent Selective For Arterial Wall Imaging
Non-invasive imaging procedures to identify atherosclerotic lesions in peripheral or coronary vessels are currently limited. A discovery program identified a low molecular weight gadolinium chelate (BMS753951) that localized preferentially in the arterial wall and facilitated non-invasive MR imaging of the location, total lesion burden and remodeling associated with atherosclerosis. When tested ex-vivo, [153Gd] labeled BMS753951 had high binding to normal and plaque bearing rabbit aorta, normal pig and cow coronaries and human plaque bearing carotid artery. In contrast, [153Gd]DTPA (Magnevist) showed >28 fold lower association with these vessels. Interestingly, BMS753951 showed little binding to rabbit vena cava. The in vivo uptake and retention of radiolabeled BMS753951 was examined in two plaque bearing animal models, the ApoE knockout mouse and the aorta angioplasty stripped rabbit model. Measurement of [153Gd] BMS753951 levels in tissues following administration (15–120 min) indicated high preferential accumulation of [153Gd] BMS753951 in the plaque bearing aorta of the rabbit (0.14 %ID/g) and ApoE mouse (10–15 %ID/g) when administered at tracer levels. In contrast, ApoE mouse aorta uptake for [153Gd]Ominscan, [153Gd]Optimark and [153Gd] Magnevist was only 0.5 to 0.9 %ID/g. The uptake of [153Gd] BMS753951 in the mouse aorta increased with dose but started to deviate from linearity at 0.2 mmol/kg. Examination of the plaque-bearing rabbit aorta by autoradiography indicated a double ring pattern of uptake with higher levels of compound seen in the media and plaque cap regions. BMS753951 demonstrated strong MR relaxivity in rabbit aorta (15 mM−1*sec−1 at 1.5 T) and when dosed (0.05 mmol/kg) to ApoE mice produced, by 15 minutes, clear aortic wall enhancement with T1 weighted spin echo MRI. Dosing of plaque bearing rabbits at 0.1 mmol/kg with BMS753951 again produced marked aorta enhancement with MRI with no enhancement of the vena cava. BMS753951 enhanced aorta images allowed luminal perimeter, exterior perimeter and wall area measurements and had good agreement with serial measurements done on histological sections. BMS753951 represents an exciting new class of tissue selective MR contrast agents for arterial wall imaging.