Comparative study of iodine-123-labeled hypericin and (99m)Tc-labeled hexakis [2-methoxy isobutyl isonitrile] in a rabbit model of myocardial infarction.

Identification of myocardial infarction (MI) by imaging is critical for clinical management of ischemic heart disease. Iodine-123-labeled hypericin (¹²³I-Hyp) is a new potent infarct avid agent. We sought to compare target selectivity and organ distribution between ¹²³I-Hyp and the myocardial perfusion agent, technetium-99m-labeled hexakis [2-methoxy isobutyl isonitrile] ((99m)Tc-Sestamibi) in rabbits with acute MI. Hypericin was radiolabeled with I using iodogen as oxidant, and (99m)Tc-Sestamibi was prepared from a commercial kit and radioactive sodium pertechnetate. Rabbits (n = 6) with 24-hour-old MI received ¹²³I-Hyp intravenously and received (99m)Tc-Sestamibi 9 hours later. They were studied by dual-isotope simultaneous acquisition micro single photon emission computed tomography/computed tomography (DISA-µSPECT/CT), tissue gamma counting (TGC), autoradiography, and histology. After purification, ¹²³I-Hyp was obtained with radiochemical purity around 99%. DISA-µSPECT/CT images showed ¹²³I-Hyp retention in infarcted but not in normal myocardium. By TGC, accumulation values reached 1.175 ± 0.096 percentage of injected dose per gram (%ID/g) and 0.028 ± 0.007%ID/g in infarcted myocardium and normal myocardium with high tracer concentration in liver, intestines, and gallbladder. (99m)Tc-Sestamibi was prepared with radiochemical purity over 95%. DISA-µSPECT/CT showed no accumulation in MI and high initial radioactivity levels in normal myocardium that were rapidly cleared as confirmed by TGC (0.011 ± 0.003%ID/g). Liver and intestines were clearly visualized. By TGC, gallbladder and kidneys show moderate (99m)Tc-Sestamibi uptake. The selectivity of ¹²³I-Hyp for infarcted myocardium and (99m)Tc-Sestamibi for normal myocardium was confirmed. ¹²³I-Hyp distribution in rabbits is characterized by hepatobiliary excretion. (99m)Tc-Sestamibi undergoes hepatorenal elimination.

Synthesis and biological evaluation of 68Ga-bis-DOTA-PA as a potential agent for positron emission tomography imaging of necrosis.

INTRODUCTION: Necrosis is a form of cell death that occurs in a variety of pathological conditions but can also be the result of therapy in cancer treatment. A radiotracer that could image necrotic cell death using PET could therefore be a useful tool to provide relevant information on the disease activity or therapeutic efficacy and assist in diagnosis and therapy management of several disorders. Pamoic acid derivatives have previously been reported to show a selective uptake in tissue undergoing cellular death via necrosis. In this study 4,4'-methylene-bis(2-hydroxy-3-naphthoic hydrazide) (pamoic acid bis-hydrazide) was conjugated to the macrocyclic ligand DOTA and labeled with the generator produced positron emitter (68)Ga. The resulting complex ((68)Ga-bis-DOTA-PA; (68)Ga-3) was evaluated as a potential radiotracer for imaging tissues undergoing cellular death via necrosis. METHODS: Bis-DOTA-PA was synthesized and labeled with (68)Ga. Biodistribution of (68)Ga-3 and analysis of plasma were studied in normal NMRI mice. Binding of the complex to necrotic tissue was first evaluated by in vitro autoradiography. Further evaluation of the uptake in necrotic tissue was performed in two different models of necrosis using microPET imaging in correlation with ex vivo autoradiography, biodistribution studies and histochemical staining. A biodistribution study in a mouse model of hepatic apoptosis was performed to study the selectivity of the uptake of (68)Ga-bis-DOTA-PA in necrotic tissue. RESULTS: (68)Ga-3 was obtained with a decay-corrected radiochemical yield of 51.8% ± 5.4% and a specific activity of about 12 GBq/µmol. In normal mice, the complex was slowly cleared from blood, mainly through the renal pathway, and showed high in vivo stability. (68)Ga-bis-DOTA-PA displayed high and selective uptake in necrotic tissue and allowed imaging of necrotic tissue using microPET. CONCLUSION: (68)Ga-3 was synthesized and characterized. In vitro, in vivo and ex vivo studies showed that the complex displays high and selective uptake in tissue undergoing cellular death via necrosis.