Evaluation of the Novel Myocardial Perfusion Positron-Emission Tomography Tracer 18F-BMS-747158-02: Comparison to 13N-Ammonia and Validation With Microspheres in a Pig Model

Background— Positron-emission tomography (PET) tracers for myocardial perfusion are commonly labeled with short-lived isotopes that limit their widespread clinical use. 18F-BMS-747158-02 (18F-BMS) is a novel pyridaben derivative that was evaluated for assessment of myocardial perfusion by comparison with 13N-ammonia (13NH3) and with radioactive microspheres in a pig model. Methods and Results— Fourteen pigs injected with 500 MBq of 13NH3 or 100 to 200 MBq of 18F-BMS underwent dynamic PET at rest and during pharmacological stress. In 8 of these pigs, 18F-BMS was injected during stress combined with transient, 2.5-minute constriction of the left anterior descending coronary artery. Radioactive microspheres were coinjected with 18F-BMS. Ratios of myocardial tracer uptake to surrounding tissues were determined, and myocardial blood flow was quantified by compartmental modeling. Both tracers showed high and homogeneous myocardial uptake. Compared with 13NH3, 18F-BMS showed higher activity ratios between myocardium and blood (rest 2.5 versus 4.1; stress 2.1 versus 5.8), liver (rest 1.2 versus 1.8; stress 0.7 versus 2.0), and lungs (rest 2.5 versus 4.2; stress 2.9 versus 6.4). Regional myocardial blood flow assessed with 18F-BMS PET showed good correlation (r=0.88, slope=0.84) and agreement (mean difference −0.10 [25th percentile −0.3, 75th percentile 0.1 mL · min−1 · g−1]) with that measured with radioactive microspheres over a flow range from 0.1 to 3.0 mL · min−1 · g−1. The extent of defects induced by left anterior descending coronary artery constriction measured by 18F-BMS and microspheres also correlated closely (r=0.63, slope=1.1). Conclusions— 18F-BMS-747158-02 is a very attractive new PET perfusion tracer that allows quantitative assessment of regional myocardial perfusion over a wide flow range. The long half-life of 18F renders this tracer useful for clinical PET/CT applications in the workup of patients with suspected or proven coronary artery disease.

[1]  G. Paradies,et al.  Decrease in Mitochondrial Complex I Activity in Ischemic/Reperfused Rat Heart: Involvement of Reactive Oxygen Species and Cardiolipin , 2004, Circulation research.

[2]  Teresa Houston,et al.  Impact of Myocardial Perfusion Imaging with PET and 82Rb on Downstream Invasive Procedure Utilization, Costs, and Outcomes in Coronary Disease Management , 2007, Journal of Nuclear Medicine.

[3]  O Muzik,et al.  Validation of nitrogen-13-ammonia tracer kinetic model for quantification of myocardial blood flow using PET. , 1993, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[4]  D E Kuhl,et al.  Noninvasive quantification of regional blood flow in the human heart using N-13 ammonia and dynamic positron emission tomographic imaging. , 1990, Journal of the American College of Cardiology.

[5]  S. Robinson,et al.  Assessment of 18F-labeled mitochondrial complex I inhibitors as PET myocardial perfusion imaging agents in rats, rabbits, and primates , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[6]  M. D. Di Carli,et al.  New technology for noninvasive evaluation of coronary artery disease. , 2007, Circulation.

[7]  William H. Press,et al.  Numerical recipes in C , 2002 .

[8]  S. Robinson,et al.  Mechanism of uptake and retention of F-18 BMS-747 158-02 in cardiomyocytes: a novel PET myocardial imaging agent , 2007, Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology.

[9]  J. Leppo,et al.  Myocardial uptake of 99mTc-tetrofosmin, sestamibi, and 201Tl in a model of acute coronary reperfusion. , 1996, Circulation.

[10]  René M. Botnar,et al.  A New 18F-Labeled Myocardial PET Tracer: Myocardial Uptake After Permanent and Transient Coronary Occlusion in Rats , 2008, Journal of Nuclear Medicine.

[11]  L. Becker,et al.  Assessment of Severity of Coronary Artery Stenosis in a Canine Model Using the PET Agent 18F-Fluorobenzyl Triphenyl Phosphonium: Comparison with 99mTc-Tetrofosmin , 2007, Journal of Nuclear Medicine.

[12]  M. Phelps,et al.  First human study of BMS747158, a novel F-18 labeled tracer for myocardial perfusion imaging , 2008 .

[13]  Michael Kreissl,et al.  Positron emission tomography-measured abnormal responses of myocardial blood flow to sympathetic stimulation are associated with the risk of developing cardiovascular events. , 2005, Journal of the American College of Cardiology.

[14]  M. Cerqueira,et al.  Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association , 2002, The international journal of cardiovascular imaging.

[15]  P. Kaufmann,et al.  Myocardial blood flow measurement by PET: technical aspects and clinical applications. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[16]  N. Mullani,et al.  Coronary flow and flow reserve by PET simplified for clinical applications using rubidium-82 or nitrogen-13-ammonia. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[17]  R. Gropler,et al.  Journey to find the ideal PET flow tracer for clinical use: Are we there yet? , 2007, Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology.

[18]  D. Pennell,et al.  A comparison of three radionuclide myocardial perfusion tracers in clinical practice: the ROBUST study , 2002, European Journal of Nuclear Medicine and Molecular Imaging.

[19]  R Guzzardi,et al.  Simultaneous in vitro and in vivo validation of nitrogen-13-ammonia for the assessment of regional myocardial blood flow. , 1990, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[20]  I. Olivotto,et al.  Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. , 2003, The New England journal of medicine.

[21]  D. Neglia,et al.  Prognostic Role of Myocardial Blood Flow Impairment in Idiopathic Left Ventricular Dysfunction , 2002, Circulation.

[22]  Brian H Annex,et al.  Translational physiology: porcine models of human coronary artery disease: implications for preclinical trials of therapeutic angiogenesis. , 2003, Journal of applied physiology.

[23]  J. Casida,et al.  The insecticide target in the PSST subunit of complex I. , 2001, Pest management science.

[24]  Stephan G. Nekolla,et al.  Reproducibility of polar map generation and assessment of defect severity and extent assessment in myocardial perfusion imaging using positron emission tomography , 1998, European Journal of Nuclear Medicine.

[25]  S. Rohrbach,et al.  Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression. , 2002, Journal of the American College of Cardiology.

[26]  S. Nekolla,et al.  Initial Characterization of an 18F-Labeled Myocardial Perfusion Tracer , 2008, Journal of Nuclear Medicine.

[27]  Mary Guaraldi,et al.  BMS-747 158-02: A novel PET myocardial perfusion imaging agent , 2007, Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology.

[28]  M. Schwaiger,et al.  Coronary stenting plus platelet glycoprotein IIb/IIIa blockade compared with tissue plasminogen activator in acute myocardial infarction. Stent versus Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction Study Investigators. , 2000, The New England journal of medicine.

[29]  Raymond Kwong,et al.  Diagnostic accuracy of rubidium-82 myocardial perfusion imaging with hybrid positron emission tomography/computed tomography in the detection of coronary artery disease. , 2007, Journal of the American College of Cardiology.

[30]  J I Hoffman,et al.  Blood flow measurements with radionuclide-labeled particles. , 1977, Progress in cardiovascular diseases.

[31]  Michael G Stabin,et al.  Radiopharmaceuticals for Nuclear Cardiology: Radiation Dosimetry, Uncertainties, and Risk , 2008, Journal of Nuclear Medicine.

[32]  M. Cerqueira,et al.  Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. , 2002, Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology.

[33]  W. Hirth,et al.  The Noah's Ark experiment: species dependent biodistributions of cationic 99mTc complexes. , 1989, International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology.