Delineation of the border zone of ischemic rabbit myocardium by a technetium-labeled nitroimidazole

Rocco, Richard J. Di; Bauer, A.; Pirro, John P.; Kuczynski, Bruce L.; Belnavis, Lilian; Chan, Yee-Wai; Linder, Karen E.; Narra, Ramakrishna; Nowotnik, David P.; Nunn, Adrian D.

doi:10.1016/0969-8051(95)02035-7

Cited by 10 publications

(13 citation statements)

References 20 publications

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“…Alternatively, the initial hypoxic stimulus could be evaluated. Radiotracers containing nitroimidazole moieties have been shown to accumulate in ischemic myocardium in an amount related inversely to tissue oxygen content, supporting the idea that nitroimidazoles may potentially be used to identify the hypoxic myocardium (5,22,23). One of the most promising technetium-99m-labeled candidates for evaluation of tissue hypoxia is oxo[3,3,9,9-tetramethyl-5-oxa-6-(2-nitro-1H-imidazol-1yl)-4,8-diazaundecane-2,10-dione dioximato](3-)-N,NЈ,NЈЈ,NЈЈЈtechnetium ( 99m Tc-BRU59-21) (11).…”

mentioning

confidence: 75%

Targeted imaging of hypoxia-induced integrin activation in myocardium early after infarction

Kalinowski¹,

Dobrucki²,

Meoli³

et al. 2008

Journal of Applied Physiology

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The alphavbeta3-integrin is expressed in angiogenic vessels in response to hypoxia and represents a potential novel target for imaging myocardial angiogenesis. This study evaluated the feasibility of noninvasively tracking hypoxia-induced alphavbeta3-integrin activation within the myocardium as a marker of angiogenesis early after myocardial infarction. Acute myocardial infarction was produced by coronary artery occlusion in rodent and canine studies. A novel (111)In-labeled radiotracer targeted at the alphavbeta3-integrin ((111)In-RP748) was used to localize regions of hypoxia-induced angiogenesis early after infarction. In rodent studies, the specificity of (111)In-RP748 for alphavbeta3-integrin was confirmed with a negative control compound ((111)In-RP790), and regional uptake of these compounds correlated with (201)Tl perfusion and a (99m)Tc-labeled nitroimidazole (BRU59-21), which was used as a quantitative marker of myocardial hypoxia. The ex vivo analysis demonstrated that only (111)In-RP748 was selectively retained in infarcted regions with reduced (201)Tl perfusion and correlated with uptake of BRU59-21. In canine studies, myocardial uptake of (111)In-RP748 was assessed using in vivo single-photon-emission computed tomography (SPECT), ex vivo planar imaging, and gamma well counting of myocardial tissue and correlated with (99m)Tc-labeled 2-methoxy-2-methyl-propyl-isonitrile ((99m)Tc-sestamibi) perfusion. Dual-radiotracer in vivo SPECT imaging of (111)In-RP748 and (99m)Tc-sestamibi provided visualization of (111)In-RP748 uptake within the infarct region, which was confirmed by ex vivo planar imaging of excised myocardial slices. Myocardial (111)In-RP748 retention was associated with histological evidence of alphavbeta3-integrin expression/activation in the infarct region. (111)In-RP748 imaging provides a novel noninvasive approach for evaluation of hypoxia-induced alphavbeta3-integrin activation in myocardium early after infarction and may prove useful for directing and evaluating angiogenic therapies in patients with ischemic heart disease.

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confidence: 75%

Targeted imaging of hypoxia-induced integrin activation in myocardium early after infarction

Kalinowski¹,

Dobrucki²,

Meoli³

et al. 2008

Journal of Applied Physiology

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“…In the two-dimensional cross-sectional geometry of the model, the ischaemic region was defined as the transmural area affected by the lack of blood flow following LAD occlusion (Figure 1), as described in experimental studies using rabbit hearts. 26,27 The ischaemic substrate during the first 10 min post-occlusion was represented by changes in membrane dynamics due to hyperkalaemia, acidosis, and hypoxia, as done previously. 12,17,20,21,[28][29][30] Specifically, [K + ] o was increased, whereas the maximum conductances of Na + and L-type Ca 2+ channels were decreased (via scaling factors S Na and S CaL ) to represent inhibition by acidosis.…”

Section: Representation Of Transmural Electrophysiological Heterogenementioning

confidence: 99%

“…Specifically, the central ischaemic zone (CIZ) was surrounded by lateral, endocardial, and epicardial border zones (BZs), which provided a transition in ischaemic parameters between the CIZ and the normal zone, as measured experimentally. 26,[31][32][33][34][35][36][37] In the absence of adequate data on the profile of ischaemic changes through the BZ, the transitions were assumed to be linear. 17 In our model, the width of the lateral BZ for [K + ] o was 5.5 mm, whereas epi-and endocardial [K + ] o BZs were 1 mm wide, consistent with experimental data.…”

Section: Representation Of Transmural Electrophysiological Heterogenementioning

confidence: 99%

Mechanistic investigation into the arrhythmogenic role of transmural heterogeneities in regional ischaemia phase 1A

et al. 2007

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“…I/N ratios from the present investigation agree well with reports on other 99m Tc-labelled nitroimidazole compounds. For BMS-181321, I/N ratios of 3-4 were reported in low-flow ischaemia in rats [10], rabbits [12] and dogs [4].…”

Section: Discussionmentioning

confidence: 98%

“…By deleting the nitroimidazole group from the parent compound, two reports showed that ischaemic myocardial uptake of BMS-181321 in vitro [13] and in vivo [12] depends almost exclusively on the nitroimidazole moiety. In contrast, deletion of the NO 2 group from 99m TcO(BAT-NI) changed neither relative ischaemic uptake on autoradiographs nor the absolute uptake in the biodistribution experiments.…”

Section: Discussionmentioning

confidence: 99%

99mTcO(BAT-NI), a novel nitroimidazole tracer: in vivo uptake studies in ischaemic myocardium

Hoffend

Linke

Mohammed

et al. 2003

Eur J Nucl Med Mol Imaging

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Myocardial perfusion single-photon emission tomography (SPET) performed with cationic technetium-99m complexes indicates ischaemic areas as cold lesions. By contrast, nitroimidazole derivatives labelled with fluorine-18 or (99m)Tc have recently shown promising results for hot spot imaging of ischaemic myocardium. This study evaluates (99m)TcO(BAT-NI), a new (99m)Tc complex comprising the nitroimidazole ligand, 2,10-dimercapto-2,10-dimethyl-4,8-diaza-6-[4-(2-nitroimidazolyl)butyl]undecane, in a low-flow in vivo model of myocardial ischaemia in thoracotomised rats. To elucidate the influence of the 2-nitroimidazole group on ischaemia-induced uptake, comparisons with ligand derivatives were performed where (a) the 2-nitro group was deleted [(99m)TcO(BAT-I)], (b) the 2-nitroimidazole functionality was replaced by a Br atom [(99m)TcO(BAT-Br)] and (c) the (99m)TcO(BAT) moiety was replaced by an iodine-125 iodophenoxybutyl ligand ((125)IP-NI). The radiolabelled compounds were i.v. injected 15 min after reducing resting myocardial blood flow by 50-60% and the uptake of radioactivity was assessed 90 min post injection. Autoradiography of left ventricular short-axis slices showed median uptake ratios of ischaemic/non-ischaemic myocardium (I/N) of 3.4, 4.5 and 3.4 for (99m)TcO(BAT-NI), (99m)TcO(BAT-I) and (99m)TcO(BAT-Br), respectively. In contrast, (125)IP-NI was not preferentially taken up by ischaemic myocardium. Accumulation of (99m)TcO(BAT-NI) in ischaemic heart regions was comparable to that in the liver. Biodistribution studies showed a median uptake of 0.65% ID/g of (99m)TcO(BAT-NI) in ischaemic tissue and an I/N of 3.3. On planar images of the thorax and upper abdomen the ischaemic hearts were visualised faintly; the median heart to lung count ratio for (99m)TcO(BAT-NI) was 1.7, and the median heart to liver count ratio was 1.0. We conclude that uptake of (99m)TcO(BAT-NI) in ischaemic myocardium does not depend on the nitroimidazole moiety but is intrinsic to the BAT complex. Clinical use of the (99m)TcO(BAT)-labelled tracers seems unlikely owing to their low uptake and their low ischaemic tissue contrast on planar images in vivo.

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Delineation of the border zone of ischemic rabbit myocardium by a technetium-labeled nitroimidazole

Cited by 10 publications

References 20 publications

Targeted imaging of hypoxia-induced integrin activation in myocardium early after infarction

Targeted imaging of hypoxia-induced integrin activation in myocardium early after infarction

Mechanistic investigation into the arrhythmogenic role of transmural heterogeneities in regional ischaemia phase 1A

99mTcO(BAT-NI), a novel nitroimidazole tracer: in vivo uptake studies in ischaemic myocardium

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