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

Abstract

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.

PET imaging of cardiac hypoxia: Opportunities and challenges

“…The uptake mechanism is thought to be common across this family of tracers, with various structural modifications being employed to improve upon the basic pharmacokinetic limitations of the parent misonidazole compound. Each has met with varying degrees of success, but so far all experience the same limitations, to a greater or lesser degree, as 18 FMISO, which we describe here [55]. For a more detailed account of the history and current state of the art in SPECT-based nitroimidazole derivatives, we direct the reader to the excellent reviews by Sinusas, Strauss et al and more recently, Krohn et al [4,56,57].…”

30 Inorganic pharmaceuticals

“…106 Bifunctional complexes of the S2N2 type with Tc-99m linked to nitroimidazoles for imaging hypoxia show hypoxia selectivity independently of the nitroimidazole group. 107 Direct labelling (i.e. without a bifunctional chelator) of small peptides has been problematic in the past, but examples continue to appear.…”

Molecular imaging: The latest generation of contrast agents and tissue characterization techniques

“…Misonidazole analogs and 2‐nitroimadazole analogs have been labeled with 123 I and 99m Tc for SPECT, and F‐18 for PET imaging of hypoxia. These agents have demonstrated increased uptake in hypoxic and low flow ischemic myocardium and brain as well as in tumors [Parliament et al, 1992; Ballinger et al, 1996; Cook et al, 1998; Melo et al, 2000; Markus et al, 2002; Tolvanen et al, 2002; Hoffend et al, 2003; Song et al, 2003]. 99m Tc labeled HL91 and BRU 59‐21 as well as F‐18 labeled fluoromisonidazole ( 18 F‐FMISO) have been recently been used to study temporal changes in tumor hypoxia in patients undergoing radiation and chemotherapy for primary and recurrent squamous head and neck carcinoma [Rischin et al, 2001; Van De Wiele et al, 2001; Hoebers et al, 2002].…”