Rapid noninvasive detection of experimental atherosclerotic lesions with novel 99mTc-labeled diadenosine tetraphosphates

Department of Radiology, Massachusetts General Hospital, Boston, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/1998; 95(2):691-5. DOI: 10.1073/pnas.95.2.691
Source: PubMed


The development of a noninvasive imaging procedure for identifying atherosclerotic lesions is extremely important for the clinical management of patients with coronary artery and peripheral vascular disease. Although numerous radiopharmaceuticals have been proposed for this purpose, none has demonstrated the diagnostic accuracy required to replace invasive angiography. In this report, we used the radiolabeled purine analog, 99mTc diadenosine tetraphosphate (Ap4A; AppppA, P1,P4-di(adenosine-5')-tetraphosphate) and its analogue 99mTc AppCHClppA for imaging experimental atherosclerotic lesions in New Zealand White rabbits. Serial gamma camera images were obtained after intravenous injection of the radiolabeled dinucleotides. After acquiring the final images, the animals were sacrificed, ex vivo images of the aortas were recorded, and biodistribution was measured. 99mTc-Ap4A and 99mTc AppCHClppA accumulated rapidly in atherosclerotic abdominal aorta, and lesions were clearly visible within 30 min after injection in all animals that were studied. Both radiopharmaceuticals were retained in the lesions for 3 hr, and the peak lesion to normal vessel ratio was 7.4 to 1. Neither of the purine analogs showed significant accumulation in the abdominal aorta of normal (control) rabbits. The excised aortas showed lesion patterns that were highly correlated with the in vivo and ex vivo imaging results. The present study demonstrates that purine receptors are up-regulated in experimental atherosclerotic lesions and 99mTc-labeled purine analogs have potential for rapid noninvasive detection of plaque formation.

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    • "Up-regulation of functional P2Y receptors also occurs in the basilar artery of the rat double-hemorrhage model [7], in the coronary artery of diabetic dyslipidemic pigs [8], and in human atherosclerotic lesions (Seye and Desgranges, unpublished data). It has been proposed that up-regulation of P2Y receptors could be a potential diagnostic indicator for the early stages of atherosclerosis [9]. Interestingly, a more recent study showed that high shear stress associated with vascular diseases can selectively up-regulate P2Y2 and P2Y6 receptors in perfused arterial SMC [101]. "
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    ABSTRACT: Atherosclerosis is an immunoinflammatory process that involves complex interactions between the vessel wall and blood components and is thought to be initiated by endothelial dysfunction [1-3]. Extracellular nucleotides that are released from a variety of arterial and blood cells [4] can bind to P2 receptors and modulate proliferation and migration of smooth muscle cells (SMC), which is known to be involved in intimal hyperplasia that accompanies atherosclerosis and postangioplasty restenosis [5]. In addition, P2 receptors mediate many other functions, including platelet aggregation, leukocyte adherence, and arterial vasomotoricity. A direct pathological role of P2 receptors is reinforced by recent evidence showing that up-regulation and activation of P2Y(2) receptors in rabbit arteries mediates intimal hyperplasia [6]. In addition, up-regulation of functional P2Y receptors also has been demonstrated in the basilar artery of the rat double-hemorrhage model [7] and in coronary arteries of diabetic dyslipidemic pigs [8]. It has been proposed that up-regulation of P2Y receptors may be a potential diagnostic indicator for the early stages of atherosclerosis [9]. Therefore, particular effort must be made to understand the consequences of nucleotide release from cells in the cardiovascular system and the subsequent effects of P2 nucleotide receptor activation in blood vessels, which may reveal novel therapeutic strategies for atherosclerosis and restenosis after angioplasty.
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