99mTc-Sestamibi

*AN"UCERIUSs(OJJAT!HMADZADEHFAR (ANS *àRGEN"IERSACK %DITORS

99mTc-Sestamibi

#LINICAL!PPLICATIONS Editors Priv.-Doz. Dr. med. Jan Bucerius Dr. med. Hojjat Ahmadzadehfar Department of Nuclear Medicine and Universitätsklinikum Bonn Cardiovascular Research Institute Klinik und Poliklinik für Nuklearmedizin Maastricht (CARIM) Sigmund-Freud-Str. 25 Maastricht University Medical Center 53127 Bonn P. Debyelaan 25 Germany 6229 HX Maastricht [email protected] The Netherlands [email protected]

Prof. Dr. med. Hans-Jürgen Biersack Universitätsklinikum Bonn Klinik und Poliklinik für Nuklearmedizin Sigmund-Freud-Str. 25 53127 Bonn Germany [email protected]

ISBN 978-3-642-04232-4 e-ISBN 978-3-642-04233-1 DOI 10.1007/978-3-642-04233-1 Springer Heidelberg Dordrecht London New York

Library of Congress Control Number: 2011937232

© Springer-Verlag Berlin Heidelberg 2012

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law.

The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protec- tive laws and regulations and therefore free for general use.

Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature.

Cover design: eStudioCalamar, Figueres/Berlin

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com) Foreword

“The owl of Minerva spreads its wings only with the break of dusk” Georg W.F. Hegel

This volume is uniquely dedicated to the applications of Technetium-99m Sestamibi scintigraphy. It presents an occasion to reflect on the remarkable career of this imag- ing radiotracer. Belonging to a family of compounds, the isonitriles, it has had a protean evolution. This family of compounds was first evaluated as a lipophilic compound excreted by the liver into the biliary tract, as a hepatobiliary imaging agent for the evaluation of hepatobiliary excretion and evaluation of gallbladder function and integrity, at a time when that imaging modality was just developing, with the search for com- pounds with better imaging properties: high affinity, rapid liver transit and excre- tion. In the course of in vivo experiments, myocardial uptake was noticed. As further experiments revealed flow-dependent myocardial uptake, high affinity and long retention time, its utility as a myocardial perfusion agent became apparent. It would turn out to be of far greater utility, and for its developer, of far greater profit as a myocardial perfusion agent than as a hepatobiliary agent. The rest is history, but it did not have to be that way. Other tracers were promising as cardiac perfusion trac- ers in animal models, but did not succeed in humans due to inter-species differences in uptake or kinetics. The timing was also fortuitous. At the time, thallium-201 reigned supreme as a myocardial imaging agent. Thallium-201 offered, with one injection, the capability for stress perfusion imaging, the detection of ischemia ver- sus myocardial scarring differentiation due to its redistribution property on delayed imaging, and information of myocardial viability, by virtue of its late redistribution. Its decay scheme produced principally low energy x-ray emissions, limiting image resolution. Its long half-life and decay scheme produced high radiation dosimetry per unit of activity, thus limiting the activity that could be administered with accept- able dosimetry. Thus, thallium-201 images were count-starved and of low resolu- tion, stimulating the search for better tracers. The development and marketing of Tc-99m sestamibi as a myocardial imaging agent came at a remarkable time, a conjunction of the development and wide- spread acceptance of SPECT imaging and the application of myocardial perfusion imaging, with thallium-201 paving the way, plus the development of coronary angioplasty, which made the localization of coronary disease important, and the

v vi &OREWORD development of non-exercise requiring stress methods, the vasodilator agents dipyridamole and adenosine, dobutamine, and their successors. Without such a conjuction, it is hard to imagine the meteoric success of sestamibi, both in its clinical utilization, and economic volume. It is said that success breeds success. The success of myocardial perfusion imag- ing, driven by sestamibi and its competitors, Tc-99m tetrofosmin and thallium, then drove development of SPECT instrumentation and software, in reconstruction, dis- play, and quantification, multiheaded gamma cameras, and more recently, attenuation correction hardware and software, and even hybrid SPECT-CT imaging, combining myocardial perfusion imaging with coronary calcium measurement and coronary angiography. This combination of events, made in heaven, has resulted in myocardial perfusion imaging accounting for some 50% of nuclear medicine imaging. Early in its myocardial perfusion agent career, sestamibi faced a question of “identity”. Was it a “perfusion agent” or a “viability agent”? The first question was easily answered early on in situations of mild to moderate coronary disease severity. In situations of severe myocardial hypoperfusion, sestamibi was shown to underes- timate perfusion and viability. This prompted the use of protocols combing stress setamibi person imaging with resting thallium-201 imaging, or combination of F-18 FDG imaging, with SPECT or PET imaging. This question stimulated early research into the mechanisms of sestamibi cell uptake and retention, and the effects of vari- ous metabolic and pharmacologic interventions. Attention turned to MIBI as a perfusion agent of other richly perfused tissues, such a skeletal muscle, in peripheral vascular disease, and uptake in metabolically active tissues, such a thyroid and parathyroid tissues. Pioneering work revealed the affinity to both types of tissue, and the fortuitous differential washout of thyroid and parathyroid tissues, led to sestamibi supplanting thallium-201, for the second time, this time in the detection and localization of parathyroid adenomas, again driven by a conjunction of sestamibi availability, SPECT and later SPECT-CT imaging, and the introduction of minimally-invasive surgery and requirement for pre-op localization. The story of the evolution of the application of sestamibi was not finished yet. It was demonstrated that sestamibi had affinity not just for normal tissues, but malig- nant tumors as well. This led to its investigation in breast cancer, lung cancer, and a wide variety of other carcinomas and sarcomas. Limited resolution and the demand for high sensitivity limited an initial success as an adjunct to mammography in breast cancer screening 20 years ago, where the demand for differentiation of even small millimeter-sized tumors outstripped planar or SPECT imaging resolution. The career of sestamibi in lung and other tumors was eclipsed by the success of F-18 fluorode- oxyglucose PET imaging, owing to the remarkable affinity of FDG for tumors of all types, combined with the higher resolution of PET imaging. Sestamibi imaging is making a remarkable come-back with the introduction of dedicated small detectors and solid state technology, that allow the close proximity of the detector to breast tumors, not achievable 20 years ago, that allow the detection of tumors of even a few millimeters, of great value in women with high density breasts, where differentiation of malignant breast tumors from glandular or fibrous tissue is difficult. &OREWORD vii

The retention of sestamibi in tissue has been found to depend not only on perfu- sion, uptake and mitochondrial binding, but also on transport of the tracer out of tissue cells. In a number of tumors, the mechanism responsible for transport of ses- tamibi out the cells is also responsible for the transport of a number of various chemotherapeutic agents, which in turn limits their cytotoxicity, thus limiting their effectiveness, a property that various from individual to individual, that even evolves in the course any particular individual’s cancer. Thus, the retention of sestamibi in a particular tumor is an index of its sensitivity to these cytotoxic drugs. This property has not yet found a place in routine clinical treatment of cancer, although its poten- tial in individualized care has been suggested. As this volume shows, applications in other tumors offer intriguing possibilities. The protean nature of Tc-99m sestamibi and its evolution as a radiotracer of many interesting properties, demonstrates its utility as a valuable tracer with mul- tiple demonstrated and potential applications, whose full utility still remains to be developed, or even to be discovered.

Director, Division of Nuclear Medicine Josef Machac, MD The Mount Sinai Medical Center New York, NY

Preface

Hexakis-2-methoxy-2-methylpropyl-isontrile technetium-99m (99mTc-Sestamibi) is a single photon emission computed tomography (SPECT-) radiotracer which was firstly introduced to clinical routine in nuclear medicine for myocardial perfusion imaging more than two decades ago. Since that time, several different, non-cardiac applications of 99mTc-Sestamibi have been reported in the literature although its main application still remains the imaging of myocardial perfusion. It was as early as 1989, that benign and malignant lung tumors were depicted by abnormal uptake of 99mTc-Sestamibi. Subsequently, further clinical studies have been performed in several oncologic (e.g., brain-, breast-, thyroid cancer) but also in non-oncologic diseases (e.g., thyroid adenoma, parathyroid adenomas). These manifold applica- tions make 99mTc-Sestamibi an interesting radiotracer in the clinical as well as the out-patient setting even despite the fast-growing diffusion of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) as an accepted and well-proven imaging technique for several oncologic and non-oncologic diseases. “99mTc-Sestamibi - Clinical Applications” aims to provide an overview of almost all oncologic and non-oncologic applications of 99mTc-Sestamibi including several rather rare indications. It includes not only different disease-related protocols of the tracer but also a comprehensive summary of the pathology and epidemiology of the accordant disease. Thereby, a strong emphasis was set on practical aspects of the use of this widespread SPECT-tracer including instructions for the preparation of several commercially available tracer kits.

Jan Bucerius Hojjat Ahmadzadehfar Hans-Jürgen Biersack

ix

Contents

1 Radiochemistry and Radiopharmacy of the SPECT-Tracer Technetium-99m-Hexakis-2-methoxy-2-isobutyl isonitrile (99mTc-Sestamibi) ...... 1 Stefan Guhlke 2 Physics and Radiation Exposure ...... 7 Mark Konijnenberg 3 Preparation of Tc-99m-Sestamibi ...... 25 Hojjat Ahmadzadehfar and Amir Sabet 4 Parathyroid Imaging ...... 31 Hans-Jürgen Biersack and Ursula Heiden 5 Myocardial Perfusion Scintigraphy with 99mTc-MIBI ...... 65 Hojjat Ahmadzadehfar and Amir Sabet 6 99mTc-Sestamibi Scintimammography ...... 87 Jan Bucerius 7 Tc-99m-MIBI for Thyroid Imaging ...... 133 Matthias Schmidt 8 Tc-99m Sestamibi in Miscellaneous Tumors ...... 159 Amir Sabet 9 Oncologic Applications of Sestamibi: In Vivo Imaging of Multi-Drug Resistance ...... 175 Ali Gholamrezanezhad Index ...... 191

xi