A rapid and accurate identification of necrotic myocardium is of great importance for diagnosis, risk stratification, clinical decision-making, and prognosis evaluation of
myocardial infarction. Here, we explored technetium-99m labeled
rhein derivatives for rapid imaging of the necrotic myocardium. Three
hydrazinonicotinic acid-linker-
rhein (HYNIC-linker-
rhein) derivatives were synthesized, and then, these synthetic compounds were labeled with technetium-99m using ethylenediaminediacetic
acid (
EDDA) and
tricine as coligands [99mTc(
EDDA)-HYNIC-linker-
rhein]. The
necrosis avidity of the three 99mTc-labeled
rhein derivatives was tested in a mouse model of
ethanol-induced muscular
necrosis by gamma counting, histochemical staining, and autoradiography. A lead tracer for visualization of necrotic myocardium was assessed by single photon emission computed tomography/computed tomography (SPECT/CT) imaging in a rat model with reperfused
myocardial infarction. The
necrosis avidity mechanism of the tracer was explored by
DNA binding studies in vitro and blocking experiments in vivo. Results showed that the uptake in necrotic muscles of the three 99mTc-compounds was higher than that in viable muscles (P < 0.001). Autoradiography and histochemical staining results were consistent with selective uptake of the radiotracer in the necrotic regions. Among the these tracers, 99mTc(EDDA)-HYNIC-ethylenediamine-rhein [99mTc(
EDDA)-HYNIC-2C-
rhein] displayed the best distribution profiles for imaging. The necrotic myocardium lesions were clearly visualized by SPECT/CT using 99mTc(EDDA)-HYNIC-2C-rhein at 1 h after injection. The necrotic-to-viable myocardium and necrotic myocardium-to-blood uptake ratios of 99mTc(EDDA)-HYNIC-2C-rhein were 4.79 and 3.02 at 1 h after injection.
DNA binding studies suggested HYNIC-linker-
rhein bound to
DNA through intercalation. The uptake of 99mTc(EDDA)-HYNIC-2C-rhein in necrotic muscle was significantly blocked by excessive unlabeled
rhein, with 77.61% decline at 1 h after coinjection. These findings suggested 99mTc(EDDA)-HYNIC-2C-rhein emerged as a "hot spot" imaging probe that has a potential for rapid imaging of necrotic myocardium. The
necrosis avidity mechanism of 99mTc(EDDA)-HYNIC-linker-rhein may be due to its interaction with exposed
DNA in necrotic tissues.