[Bis[1,2-cyclohexanedione dioxamato(1-)-O]-[1,2-cyclohexanedioneioximato(2-)-O]methylborato(2-)-N,N′,N″,N′″,N″″,N′″″]-chlorotechnetium-99m (hereinbelow, “Tc-99m teboroxime” or just “teboroxime”) is a radiopharmaceutical agent indicated for cardiac imaging, particularly for myocardial perfusion imaging to distinguish normal from abnormal myocardium in patients with suspected coronary artery disease (CAD) using rest and stress techniques. Teboroxime, which a member of a class of radiopharmaceuticals known as boronic acid adducts of technetium dioxime (“BATO” compounds), is a neutral, lipophilic agent labeled with technetium Tc-99m that is used for myocardial perfusion imaging (Narra [1989], all references cited hereinbelow). Teboroxime has the advantage of using Tc-99m (6 hours half-life and 140 keV photon energy) as the imaging radionuclide, while maintaining linear uptake with flow at high flow rates (Chiao [1994]). Its very high extraction (Leppo [1990]) potentially makes it an excellent perfusion agent for detecting mild to moderate severity coronary disease with high sensitivity and specificity. The rapid clearance characteristics of teboroxime potentially allows serial testing (rest, peak stress, and washout) in a contracted time frame, which also makes teboroxime valuable for use in clinical imaging.
Teboroxime is described in U.S. Pat. No. 4,705,849 to Nunn et al., which is incorporated herein by reference. Technetium-99m as a pertechnetate ion containing salt is combined with a source of anion, a boronic acid derivative having the formula
or a pharmaceutically acceptable salt thereof, wherein R7 is hydrogen, alkyl or aryl, and a dioxime having the formula
or a pharmaceutically acceptable salt thereof. The size of the host, and the imaging system used, are described as determining the quantity of radioactivity needed to produce diagnostic images. For a human host, the quantity of radioactivity injected normally ranges from about 5 to 20 millicuries (mCi) of technetium-99m.
U.S. Pat. No. 6,056,941 to Schramm et al., which is incorporated herein by reference, describes a kit for forming teboroxime in situ in the presence of hydroxypropyl gamma cyclodextrin to maintain the solution free of particulate matter originating from the formulation. The teboroxime formed has a radiation dose of 10 to 100 mCi.
Reference is made to FIG. 1, which is a graph from Case et al. (2001), cited hereinbelow, which shows the average teboroxime uptake as a function of time post-injection for the heart, liver, and background. One of the known drawbacks of teboroxime is that once it returns to the blood, it is readily taken up by the liver and other sub-diaphragmatic structures which potentially “obscure” the inferior wall of the heart. Thus, there is a short window of opportunity for imaging the post-injection perfusion pattern during which there is a peak heart to background ratio. Although teboroxime was approved for marketing by the U.S. Food and Drug Administration in 1991, it was subsequently discontinued by the manufacturer. Teboroxime “was not marketed because of limitations of hardware (nuclear cameras) and software of that era. Recently, Bracco Diagnostics, Inc. acquired the product and is planning to reintroduce it providing that an imaging protocol that capitalizes on its unique kinetics and software for processing, display and quantitation can be developed” (Case et al. [2001]).
Stewart R E et al., in “Myocardial clearance kinetics of technetium-99m-SQ30217: a marker of regional myocardial blood flow,” J Nucl Med 31:1183-1190 (1990), which is incorporated herein by reference, describe a study that evaluated the myocardial tracer kinetics of technetium-99m-SQ30217 (teboroxime). The authors note that “Currently employed single- and dual-head tomography does not provide the necessary temporal resolution to delineate the kinetics of SQ30217 in the human heart. The newer multi-head SPECT systems may provide sufficient temporal resolution for the clinical application of 99mTc-SQ30217 (18)” (p. 1189).
Chua T et al., in “Technetium-99m teboroxime regional myocardial washout in subjects with an without coronary artery disease,” Am J Cardiol 72:728-734 (1993), which is incorporated herein by reference, describe a study designed “to test the hypothesis that regional myocardial washout of technetium-99m teboroxime is slowed in the presence of coronary stenosis” (abstract). Regional variability in washout rates were observed, “with the anterior and high lateral regions having the slowest washout, and the inferior wall the highest” (p. 732). “A possible explanation for this regional variation in washout rates is the effect of hepatic teboroxime uptake on the measured activity in the inferior wall. Liver uptake of teboroxime is avid, peaking 6 minutes after injection of teboroxime, and may interfere with visual assessment of the inferior wall” (p. 732).
Case T et al., in “Rapid back to back adenosine stress/rest technetium-99m teboroxime myocardial perfusion SPECT using a triple-detector camera,” J Nucl Med 34:1485-1493 (1993), which is incorporated herein by reference, describe imaging parameters and the clinical efficacy of a rapid back to back adenosine stress/rest teboroxime myocardial perfusion SPECT protocol using a triple-detector camera. The authors note that “The rapid myocardial washout of teboroxime coupled with its intense late hepatic uptake necessitates that imaging be completed more quickly than with 201Tl or 99mTc sestamibi” (p. 1485). The triple-headed camera used was able to produce “2-3 minute and 2-5 minute anterior view adenosine teboroxime (20-25 mCi) images containing 8,000-9,000 and 12,000-15,000 myocardial counts, respectively. The authors conclude, “Thus, despite the use of a triple-head detector camera and continuous acquisition, teboroxime studies with this fast protocol result in relatively low-count images” (p. 1490).
Feng B et al., in “Simultaneous assessment of cardiac perfusion and function using 5-dimensional imaging with Tc-99m teboroxime,” J Nucl Cardiol 13(3):354-61 (2006), which is incorporated herein by reference, investigated the feasibility of simultaneously imaging myocardial ischemia and transient post-stress akinesis using gated-dynamic SPECT. A gated-dynamic mathematical cardiac torso (MCAT) phantom was developed to model both teboroxime kinetics and cardiac regional wall motion. A lesion was simulated as having delayed post-stress teboroxime washout together with a transient post-stress wall motion abnormality. Gated projection data were created to represent a 3-headed SPECT system undergoing a total rotation of 480 degrees. The dynamic expectation-maximization reconstruction algorithm with post-smoothing across gating intervals by Wiener filtering, and the ordered-subset expectation maximization reconstruction algorithm with 3-point smoothing across gating intervals were compared. Compared with the ordered-subset expectation maximization with 3-point smoothing, the dynamic expectation-maximization algorithm with Wiener filtering was able to produce visually higher-quality images and more accurate left ventricular ejection fraction estimates. The authors conclude that, from simulation, changing cardiac function and tracer localization possibly can be assessed by using a gated-dynamic acquisition protocol combined with a 5-dimensional reconstruction strategy.
Sitek A et al., in “Removal of liver activity contamination in teboroxime dynamic cardiac SPECT imaging with the use of factor analysis,” J Nucl Cardiol 9(2):197-205 (2002), which is incorporated herein by reference, write, “One of the major problems associated with technetium 99m teboroxime cardiac imaging is the high concentration of activity in the liver. In some cases it is impossible to diagnose defects on the inferior wall because of the finite resolution and scatter that cause images of the inferior wall and the liver to overlap.” The least-squares factor analysis of dynamic structures method, with correction for non-unique solutions, was used to remove the liver activity from the image. The method was applied to dynamically acquired Tc-99m teboroxime data. The liver activity removal method was tested through use of computer simulations and tomographically acquired canine and patient cardiac studies. The authors report that in all studies the least-squares factor analysis of dynamic structures method was able to extract the liver activity from the series of dynamic images, thereby making it possible to remove it quantitatively from the entire series. The method is described as being used successfully to remove the liver activity that partially overlapped the inferior wall in normal hearts. The method tends to increase the contrast between defects and normal myocardial tissue in abnormal hearts. The authors conclude that the method presented can be used to assist in diagnosis of cardiac disease when dynamically acquired teboroxime data are used. Because the contrast between the defect and normal myocardial tissue can be changed, the processed image cannot be used by itself to make an accurate diagnosis. However, with the liver activity removed, the image provides additional information that is described as being very useful in the imaging of patients whose liver activity overlaps the inferior heart wall.
The following references regarding teboroxime, all of which are incorporated herein by reference, may be of interest:    “CARDIOTEC® Kit for the Preparation of Technetium Tc 99m Teboroxime For Diagnostic Use” package insert, Bracco Diagnostics (July 2003)    Bontemps L et al., “Technetium-99m teboroxime scintigraphy. Clinical experience in patients referred for myocardial perfusion evaluation,” Eur J Nucl Med 18(9):732-9 (1991)    Chua et al. in J Nucl Med in 1982    Chiao P C et al., “Compartmental analysis of technetium 99m-teboroxime kinetics employing fast dynamic SPECT at stress and rest,” J Nucl Med 35:1265-73 (1994)    Meerdink D J et al., “Experimental studies of the physiologic properties of technetium-99m agents: myocardial transport of perfusion imaging agents,” Am J Cardiol 66:9 E-15E (1990)    Leppo J A et al., “Comparative myocardial extraction of two technetium-labeled BATO derivatives (SQ30217, SQ32014) and thallium,” J Nucl Med 31:67-74 (1990)    Narra R K et al., “A neutral technetium-99m complex for myocardial imaging,” J Nucl Med 30:1830-1837 (1989)    Garcia E V et al, “Accuracy of dynamic SPECT acquisition for Tc-99m teboroxime myocardial perfusion imaging: preliminary results,” American College of Cardiology 51st Annual Scientific Session, Atlanta, Ga. (Mar. 17-20, 2002)    Case J A et al., in “Myocardial kinetics of technetium-99m teboroxime: a new radiopharmaceutical for assessing myocardial perfusion” (2001)    Case J A et al., “Reducing impact of changing liver concentration in Tc-99m-teboroxime imaging using dynamic SPECT,” Cardiovascular Imaging Technologies, Kansas City, Mo. and Emory University, Atlanta, Ga., Annual Meeting of the Society of Nuclear Medicine, Los Angeles (2002)    Reutter B W et al., “Effects of temporal modelling on the statistical uncertainty of spatiotemporal distributions estimated directly from dynamic SPECT projections,” Phys Med Biol 47(15):2673-83 (2002)    Reutter B W et al., “Accuracy and precision of compartmental model parameters obtained from directly estimated dynamic SPECT time-activity curves,” 2002 IEEE Nuclear Science Symposium and Medical Imaging Conference Records, pp. 1584-1588 (preprint) (2002)    Sitek A et al., “Correction for ambiguous solutions in factor analysis using a penalized least squares objective,” IEEE Trans Med Imaging 21(3):216-25 (2002)    Yang D J et al., “Imaging with 99 mTc ECDG targeted at the multifunctional glucose transport system: feasibility study with rodents,” Radiology 226:465-473 (2003)    El Fakhri G et al., “Quantitative dynamic cardiac 82Rb PET using generalized factor and compartment analyses,” J Nucl Med 46:1264-1271 (2005)    Dilsizian V et al., “Metabolic imaging with beta-methyl-p-[(123)I]-iodophenyl-pentadecanoic acid identifies ischemic memory after demand ischemia,” Circulation 112(14):2169-74 (2005) Epub 2005 Sep. 26    Gullberg G T et al., “Chapter 8: Dynamic Cardiac Single-Photon Emission Computed Tomography Using Fast Data Acquisition Systems,” in Zaret B L et al., Clinical Nuclear Cardiology: State of the Art and Future Directions (Elsevier Mosby, 3rd edition, 2004)    PCT Publication WO 06/051531 to Rousso et al., which is assigned to the assignee of the present application and is incorporated herein by reference, describes radioimaging methods, devices and radiopharmaceuticals. The publication describes several teboroxime preparation and imaging protocols.
U.S. Pat. No. 6,242,743 to DeVito et al., which is incorporated herein by reference, describes a tomographic imaging system which images ionizing radiation such as gamma rays or x-rays. The system is described as being capable of producing tomographic images without requiring an orbiting motion of the detector(s) or collimator(s) around the object of interest, and of observing the object of interest from sufficiently many directions to allow multiple time-sequenced tomographic images to be produced. The system consists of a plurality of detector modules which are distributed about or around the object of interest and which fully or partially encircle it. The detector modules are positioned close to the object of interest thereby improving spatial resolution and image quality. The plurality of detectors view a portion of the patient or object of interest simultaneously from a plurality of positions. These attributes are achieved by configuring small modular radiation detector with high-resolution collimators in a combination of application-specific acquisition geometries and non-orbital detector module motion sequences composed of tilting, swiveling and translating motions, and combinations of such motions. Various kinds of module geometry and module or collimator motion sequences are possible. The geometric configurations may be fixed or variable during the acquisition or between acquisition intervals.
The following patents and patent application publications, which describe gamma cameras and imaging processing techniques, and which are incorporated herein by reference, may be of interest:
US Patent Application Publication 2005/0205792 to Rousso et al.
PCT Publication WO 05/118659 to Dichterman et al.
PCT Publication WO 05/119025 to Nagler et al.
US Patent Application Publication 2004/0204646 to Nagler et al.
PCT Publication WO 06/054296 to Dickman
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PCT Publication WO 04/042546 to Kimchy et al.
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