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

Abstract

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.

Figure 1

Chemical structures of Ap₄A and AppCHClppA.

Figure 2

Blood clearance of ^99mTc-labeled Ap₄A and AppCHClppA in atherosclerotic and control rabbits. The bi-exponential fits to the data are also indicated: ^99mTc-Ap₄A in atherosclerotic rabbits (solid line), ^99mTc-Ap₄A in control rabbits (dot-dashed line), and ^99mTc-AppCHClppA in atherosclerotic rabbits (dashed line). Each point is the mean ± SEM for three animals.

Figure 3

Biodistribution of ^99mTc-Ap₄A-glucoheptonate in nontarget organs at 3 hr after administration. Each bar is the mean ± SEM for three animals.

Figure 4

Accumulation of ^99mTc-labeled Ap₄A and AppCHClppA in lesioned and normal aortic segments of rabbits at 3 hr after i.v. administration. Each bar is the mean ± SEM for three animals.

Figure 5

Images of the aorta of a rabbit with experimental atherosclerosis. In vivo gamma camera images (lateral decubitus projection) acquired at 15 min (Left) and 2 hr (Center) after injection of ^99mTc-Ap₄A. (Right) Corresponding ex vivo gamma camera image and sketch of the lesioned areas.

Figure 6

Images of the aorta of a control rabbit. In vivo gamma camera image acquired at 15 min (Left) and 2 hr (Center) after injection of ^99mTc-Ap₄A-glucoheptonate. (Right) Corresponding ex vivo gamma camera image and sketch of the lesioned areas.