Ebook Principles and practice of PET and PET/CT: Part 1

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PRINCIPLES AND
PRACTICE OF PET
AND PET/CT
SECOND EDITION

EDITOR

RICHARD L. WAHL, MD
Professor of Radiology and Oncology, Henry N. Wagner Jr Professor of Nuclear Medicine
Director, Division of Nuclear Medicine and PET
Vice Chairman for Technology and New Business Development
The Russell H. Morgan Department of Radiology and Radiological Sciences
The Johns Hopkins University School of Medicine
Baltimore, Maryland
ASSOCIATE EDITOR: CARDIOVASCULAR PET SECTION

ROBERT S.B. BEANLANDS, MD, FRCPC, FACC
Professor of Medicine (Cardiology)/Radiology
Chief, Cardiac Imaging
Director, National Cardiac PET Centre
University of Ottawa Heart Institute
Ottawa, Ontario

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Acquisitions Editor: Lisa McAllister
Managing Editor: Kerry Barrett
Project Manager: Rosanne Hallowell
Manufacturing Manager: Benjamin Rivera
Marketing Manager: Angela Panetta
Art Director: Risa Clow
Production Services: Aptara, Inc.
Second Edition
© 2009 by Lippincott Williams & Wilkins, a Wolters Kluwer business
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Philadelphia, PA 19106
LWW.com

First Editon © 2002 by Lippincott Williams & Wilkins
All rights reserved. This book is protected by copyright. No part of this book may be reproduced in
any form or by any means, including photocopying, or utilizing by any information storage and
retrieval system without written permission from the copyright owner, except for brief quotations
embodied in critical articles and reviews.
Printed in China
Library of Congress Cataloging-in-Publication Data
Principles and practice of PET and PET/CT / editor, Richard L. Wahl, Henry N. Wagner Jr. ;
associated editor, cardiovascular PET section, Robert Beanlands. — 2nd ed.
p. ; cm.
Rev. ed. of: Principles and practice of positron emission tomography / editor, Richard L. Wahl ;
associate editor, Julia W. Buchanan. c2002.
Includes bibliographical references and index.
ISBN 978-0-7817-7999-9
1. Tomography, Emission. I. Wahl, Richard L. II. Wagner, Henry N., 1927– III.
Principles and practice of positron emission tomography.
[DNLM: 1. Positron-Emission Tomography—methods. 2. Tomography, X-Ray Computed—
methods. WN 206 P9568 2009]
RC78.7.T62P75 2009
616.07’575—dc22
2008031561
Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices. However, the authors, editors, and publisher are not responsible for errors or
omissions or for any consequences from application of the information in this book and make no
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10 9 8 7 6 5 4 3 2 1



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To my wife Sandy and my children, whose generous patience and
support during my many hours of work on this book were essential to
its genesis and completion. The current state of PET/CT as a broadly
applicable method, as reflected in this text, lies squarely on the
shoulders of pioneers in nuclear medicine research, ambitious trainees,
skilled technologists, and study participants.


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CONTENTS

Contributing Authors xi
Preface xvii
Preface to the First Edition
1

xix

Production of Radionuclides for PET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Ronald D. Finn and David J. Schlyer

2

Radiotracer Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Joanna S. Fowler and Yu-Shin Ding

3

PET Physics and PET Instrumentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Timothy G. Turkington

4

Fundamentals of CT in PET/CT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Mahadevappa Mahesh

5

Data Analysis and Image Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Robert Koeppe

6

Standardized Uptake Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Richard L. Wahl

7

Image Fusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Charles A. Meyer and Richard L. Wahl

8

Oncologic Applications

8.1 Principles of Cancer Imaging with 18-F-Fluorodeoxyglucose . . . . . . . . . . . . . . . . . . . . . . . . 117
Richard L. Wahl

8.2 How to Optimize CT for PET/CT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Gerald Antoch and Andreas Bockisch

8.3 Artifacts and Normal Variants in PET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Paul Shreve

8.4 Monitoring Response to Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Anthony F. Shields

8.5 PET and PET/CT in Radiation Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
Michael P. Mac Manus and Rodney J. Hicks

8.6 Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
Michael J. Fulham and Armin Mohamed

8.7 Use of PET and PET/CT in the Evaluation of Patients
with Head and Neck Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Todd M. Blodgett, Alexander Ryan, and Barton Branstetter IV

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Contents

8.8 Thyroid Cancer and Thyroid Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
Michele Brenner and Richard L. Wahl

8.9 Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
Patrick J. Peller and Val J. Lowe

8.10 Lymphoma and Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .260
Sven N. Reske

8.11 PET and PET/CT of Malignant Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .275
Hans C. Steinert

8.12 PET in Breast Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .287
Farrokh Dehdashti

8.13 Esophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .310
Wolfgang A. Weber and Richard L. Wahl

8.14 Applications for Fluorodeoxyglucose PET and PET/CT in the Evaluation
of Patients with Colorectal Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .320
Dominique Delbeke

8.15 Pancreatic and Hepatobiliary Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .331

Oleg Teytelboym, Dominique Delbeke, and Richard L. Wahl

8.16 Cervical and Uterine Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .348
Perry W. Grigsby

8.17 PET and PET/CT in Ovarian Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .355
Hedieh Eslamy, Robert Bristow, and Richard L. Wahl

8.18 Genitourinary Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .366
Heiko Schöder

8.19 Sarcomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .392
Janet Eary

8.20 Gastrointestinal Stromal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .402
Annick D. Vanden Abbeele, Sukru M. Erturk, and Richard J. Tetrault

8.21 PET and PET/CT Imaging of Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .411
Richard P. Baum and Vikas Prasad

8.22 Carcinoma of Unknown Primary, Including Paraneoplastic
Neurological Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .438
Jennifer Rodriguez-Ferrer and Richard L. Wahl

8.23 Pediatrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .443
Hossein Jadvar, Leonard P. Connolly, Frederic H. Fahey, and Barry L. Shulkin

8.24 Hypoxia Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .464
Morand Piert

8.25 Newer Tracers for Cancer Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .472
Rodney J. Hicks

9

Neurologic Applications
9.1

Movement Disorders, Stroke, and Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .479
Nicolaas I. Bohnen

9.2

Fluorodeoxyglucose PET Imaging of Dementia: Principles and
Clinical Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .500
Satoshi Minoshima, Takahiro Sasaki, and Eric Petrie


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Contents

10

Psychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .516
Marc Laruelle and Anissa Abi-Dargham

11

Cardiac Applications
11.1

Evaluation of Myocardial Perfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .541
Keiichiro Yoshinaga, Nagara Tamaki, Terrence D. Ruddy, Rob deKemp, and Robert S.B. Beanlands

11.2

Myocardial Viability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .565
Robert S.B. Beanlands, Stephanie Thorn, Jean DaSilva, Terrence D. Ruddy, and Jamshid Maddahi

11.3

Oxidative Metabolism and Cardiac Efficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .589
Heikki Ukkonen and Robert S.B. Beanlands

11.4

Myocardial Neurotransmitter Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .607
Markus Schwaiger, Ichiro Matsunari, and Frank M. Bengel

12

PET/CT Imaging of Infection and Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . .619
Ora Israel

13

PET and Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .634
Jerry M. Collins

14

Emerging Opportunities
14.1

Imaging Gene Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .644
Uwe Haberkorn

14.2

The Kidneys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .661
Zsolt Szabo, Jinsong Xia, and William B. Mathews

14.3

Imaging the Neovasculature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .676
Ambros J. Beer, Hans-Jürgen Wester, and Markus Schwaiger

14.4

Progress in Amyloid Imaging: Five Years of Progress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .690
Brian J. Lopresti, William E. Klunk, and Chester A. Mathis

15

PET Imaging as a Biomarker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .702
Wolfgang A. Weber, Caroline C. Sigman, and Gary J. Kelloff

Index

713

ix


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C O N T R I B U T I N G AU T H O R S

Anissa Abi-Dargham, MD
Professor, Departments of Psychiatry and Radiology
Columbia University College of Physicians and Surgeons
Chief, Division of Translational Imaging
Department of Psychiatry
New York State Psychiatric Institute
New York, New York
Gerald Antoch, MD
Associate Professor, Department of Diagnostic and Interventional
Radiology and Neuroradiology
University at Duisburg-Essen
Vice Chairman, Department of Diagnostic and Interventional
Radiology and Neuroradiology
University Hospital Essen
Essen, Germany
Richard P. Baum, Professor Dr. med
Chairman and Director, Department of Nuclear Medicine/Centre
for PET/CT
Zentralklinik Bad Berka
Bad Berka, Germany
Robert S. B. Beanlands, MD, FRCPC, FACC
Professor of Medicine (Cardiology)/Radiology
Chief, Cardiac Imaging
Director, National Cardiac PET Centre
University of Ottawa Heart Institute
Ottawa, Ontario
Ambros J. Beer, PhD
Assistant Professor, Department of Nuclear Medicine
Technische Universitat München
Resident, Department of Nuclear Medicine

Klinikum rechts der Isar der TU München
Munich, Germany
Frank M. Bengel, MD
Associate Professor of Radiology and Medicine
Director of Cardiovascular Nuclear Medicine
Division of Nuclear Medicine, Department of Radiology
The Johns Hopkins Medical Institutions
Baltimore, Maryland
Todd M. Blodgett, MD
Assistant Professor
Chief of Cancer Imaging
Department of Radiology
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania

Andreas Bockisch, MD, PhD
Professor and Director
Department of Nuclear Medicine
University Hospital Essen
Essen, Germany
Nicholas I. Bohnen, MD, PhD
Associate Professor of Radiology and Neurology
Department of Radiology, Division of Nuclear Medicine
University of Michigan Medical Center
Ann Arbor, Michigan
Barton F. Branstetter IV, MD
Associate Professor and Director of Head and Neck Imaging
Departments of Radiology, Otolaryngology, and Biomedical
Informatics
University of Pittsburgh School of Medicine

Pittsburgh, Pennsylvania
Michele E. Brenner, MD
Chief Nuclear Medicine Resident, Department of Radiology
Johns Hopkins University
Baltimore, Maryland
Robert Bristow, MD
Professor, Departments of Gynecology and Obstetrics and
Oncology
The Johns Hopkins Medical Institutions
Director, Kelly Gynecologic Oncology Service
The Johns Hopkins Hospital
Baltimore, Maryland
Jerry M. Collins, PhD
Associate Director for Developmental Therapeutics
Division of Cancer Treatment and Diagnosis
National Cancer Institute
Rockville, Maryland
Leonard P. Connolly, MD
Assistant Professor
Division of Nuclear Medicine
Children’s Hospital Boston, Harvard Medical School
Boston, Massachusetts
Jean DaSilva
Associate Professor, Department of Medicine (Cardiology)
University of Ottawa
Head Radiochemist
Department of PET Centre
University of Ottawa Heart Institute
Ottawa, Ontario

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Contributing Authors

Farrokh Dehdashti, MD
Professor of Radiology, Division of Nuclear Medicine
Edward Mallinckrodt Institute of Radiology
St. Louis, Missouri
Rob deKemp, PhD
Associate Professor, Department of Medicine and Engineering
University of Ottawa
Head Imaging Physicist, Department of Cardiac Imaging
Ottawa Heart Institute
Ottawa, Ontario
Dominique Delbeke, MD, PhD
Professor and Director of Nuclear Medicine and PET
Department of Radiology and Radiological Sciences
Vanderbilt University Medical Center
Nashville, Tennessee

Yu-Shin Ding, PhD
Professor
Co-Director of Yale PET Center
Director of Radiochemistry, Department of Diagnostic
Radiology
Yale University School of Medicine
New Haven, Connecticut
Janet F. Eary, MD
Professor, Department of Nuclear Medicine
University of Washington School of Medicine
Seattle, Washington
Sukru Mehmet Erturk, MD
Attending Radiologist
Department of Radiology
Sisli Etfal Training and Research Hospital
Istanbul, Turkey
Hedieh Khalatbari Eslamy, MD
PET/CT Fellow in Clinical Oncology, Department of Radiology
Stanford University Medical Center
Stanford, California
Frederic H. Fahey, DSc
Associate Professor, Department of Radiology
Harvard Medical School
Director of Nuclear Medicine Physics
Division of Nuclear Medicine
Children’s Hospital Boston
Boston, Massachusetts
Ronald D. Finn, PhD
Chief, Radiopharmaceutical Chemistry Service
Director, Cyclotron Core Facility

Departments of Radiology and Medical Physics
Memorial Sloan-Kettering Cancer Center
New York, New York
Joanna S. Fowler, PhD
Senior Chemist
Brookhaven National Laboratory
Upton, New York

Michael J. Fulham, MBBS, FRACP
Professor, Faculty of Medicine
Adjunct Professor, School of Information Techologies
University of Sydney
Director, Department of Molecular Imaging
Royal Prince Alfred Hospital
Clinical Director of Medical Imaging Services
Sydney South West Area Health Service
Camperdown, Australia
Perry W. Grigsby, MD
Professor, Department of Radiation Oncology; Obstetrics and
Gynecology
Division of Nuclear Medicine
Mallinckrodt Institute of Radiology
Washington University School of Medicine and Alvin J. Siteman
Cancer Center
St. Louis, Missouri
Uwe Haberkorn, MD
Professor, Department of Nuclear Medicine
University Hospital
University of Heidelbert
Head, Department of Clinical Cooperation Unit Nuclear Medicine

German Cancer Research Center
Heidelberg, Germany
Rodney P. Hicks, MB BS(Hons), MD, FRACP
Professor, Department of Medicine and Radiology
The University of Melbourne
Parkville, Australia
Director and Co-chair
Translational Research Centre for Molecular Imaging and
Translational Oncology
The Peter MacCallum Cancer Centre
East Melbourne, Australia
Ora Israel, MD
Professor, B. and R. Rappaport School of Medicine
Technion-Israel Institute of Technology
Chief, Department of Nuclear Medicine
Rambam Health Care Campus
Haifa, Israel
Hossein Jadvar, MD, PhD, MPH, MBA
Associate Professor, Department of Radiology and Biomedical
Engineering
Director, Radiology Research, Keck School of Medicine
University of Southern California
Los Angeles, California
Gary J. Kelloff, MD
National Institutes of Health, National Cancer Institute
Division of Cancer Treatment and Diagnosis
Rockville, Maryland
William E. Klunk, MD, PhD
Professor, Department of Psychiatry
University of Pittsburgh School of Medicine

Pittsburgh, Pennsylvania


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Contributing Authors

xiii

Robert A. Koeppe, PhD
Professor, Department of Radiology–Nuclear Medicine
University of Michigan Medical School and Medical Center
Ann Arbor, Michigan

Ichiro Matsunari, MD, PhD
Director, Department of Clinical Research
The Medical and Pharmacological Research Center Foundation
Hakui, Japan

Marc A. Laruelle, MD
Professor, Department of Neurosciences
Imperial College
Vice President, Molecular Imaging
Clinical Pharmacology and Discovery Medicine

GlaxoSmithKline
London, England
Adjunct Professor, Department of Psychiatry and Radiology
Columbia University
New York, New York

Charles R. Meyer, PhD
Professor, Department of Radiology
University of Michigan
Ann Arbor, Michigan

Brian J. Lopresti, MD
Department of Radiology
University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania
Val J. Lowe, MD
Associate Professor and Consultant, Department of Radiology
Mayo Clinic
Rochester, Minnesota
Michael P. MacManus, MD
Associate Professor, Department of Pathology
University of Melbourne
Melbourne, Australia
Radiation Oncologist, Department of Radiation Oncology
Peter MacCallum Cancer Centre
East Melbourne, Australia
Jamshid Maddahi, MD
Clinical Professor, Department of Pharmacology and
Medicine–Cardiology
University of Los Angeles School of Medicine

Los Angeles, California
Mahadevappa Mahesh, MS, PhD, FAAPM
Assistant Professor of Radiology and Medicine
The Russell H. Morgan Department of Radiology and
Radiological Sciences
Chief Physicist, Department of Radiology
The Johns Hopkins University School of Medicine
Baltimore, Maryland
William B. Mathews, PhD
Research Associate, Department of Radiology
Division of Nuclear Medicine
The Johns Hopkins University
Baltimore, Maryland
Chester A. Mathis, PhD
Professor, Department of Radiology, Pharmacology, and
Pharmaceutical Sciences
University of Pittsburgh
Director, PET Facility, Department of Radiology
UPMC Presbyterian Hospital
Pittsburgh, Pennsylvania

Satoshi Minoshima, MD, PhD
Professor and Vice Chair, Research, Department of Radiology
University of Washington
Seattle, Washington
Armin Mohamed, MBBS, BSc, FRACP
Associate Professor, Faculty of Medicine
University of Sydney
Sydney, Australia
Senior Staff Specialist, Department of Molecular Imaging

Royal Prince Hospital
Camperdown, Australia
Patrick J. Peller, MD
Assistant Professor, Department of Radiology
Mayo Clinic
Rochester, Minnesota
Eric C. Petrie, MD, MS
Associate Professor, Department of Psychiatry and Behavioral
Sciences
University of Washington
Staff Physician, Psychiatry
Mental Health Service and Mental Illness Research Education and
Clinical Center
Veterans Affairs Puget Sound Health Care System
Seattle, Washington
Morand Piert, MD, PhD
Associate Professor and Director, Department of Radiology
Division of Nuclear Medicine
University of Michigan Health System
Ann Arbor, Michigan
Vikas Prasad. MD
Clinical Research Associate and Assistant Doctor
Department of Nuclear Medicine and Centre for PET/CT
Zentralklinik Bad Berka
Bad Berka, Germany
Sven N. Reske, MD
Professor and Director, Department of Nuclear Medicine
University of Ulm
Ulm, Germany
Jennifer Rodriguez-Ferrer, MD

Division of Nuclear Medicine
Russell H. Morgan Department of Radiology and Radiological
Sciences
The Johns Hopkins University School of Medicine
Baltimore, Maryland


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Contributing Authors

Terrence D. Ruddy, MD, FRCPC
Professor, Department of Medicine (Cardiology) and Radiology
(Nuclear Medicine)
University of Ottawa
Division Head, Department of Medicine (Cardiology) and
Radiology (Nuclear Medicine)
University of Ottawa Heart Institute and the Ottawa Hospital
Ottawa, Canada
Alexander Ryan, MD
Resident, Department of Radiology
University of Pittsburgh

Pittsburgh, Pennsylvania

Hans C. Steinert, MD
Professor, Department of Medical Radiology
Division of Nuclear Medicine
University Hospital of Zürich
Zürich, Switzerland
Zsolt Szabo, MD, PhD
Professor and Attending Physician of Nuclear Medicine,
Department of Radiology
The Johns Hopkins Medical Institutions
Baltimore, Maryland

Takahiro Sasaki, MD, PhD
Instructor, Department of Neurology
Keio University School of Medicine
Tokyo, Japan

Nagara Tamaki, MD, PhD
Professor and Director, Department of Nuclear Medicine
Hokkaido University Graduate School of Medicine
Chairman, Department of Nuclear Medicine
Hokkaido University Hospital
Sapporo, Japan

David J. Schlyer , PhD
Senior Scientist, Department of Medicine
Brookhaven National Laboratory
Upton, New York

Richard J. Tetrault, RT (N), CNMT, PET
Chief Technologist, Department of Radiology
Dana-Farber Cancer Institute
Boston, Massachusetts

Heiko Schöder, MD
Associate Professor, Department of Radiology
Weill Cornell Medical College
Associate Attending Physician, Department of Radiology/Nuclear
Medicine
Memorial Sloan Kettering Cancer Center
New York, New York

Stephanie Thorn, Msc
PhD Candidate, Department of Cellular and Molecular
Medicine
Department of Cardiac Imaging
University of Ottawa
University of Ottawa Heart Institute
Ottawa, Ontario

Markus Schwaiger, MD
Professor and Chief, Department of Nuclear Medicine
Klinikum r.d. Isar d. Tum
Munich, Germany

Timothy G. Turkington, PhD
Associate Professor, Department of Radiology, Medical Physics,
and Biomedical Engineering
Duke University

Durham, North Carolina

Anthony F. Shields, MD, PhD
Professor, Department of Medicine and Oncology
Wayne University School of Medicine
Associate Center Director for Clinical Research
Karmanos Cancer Institute
Detroit, Michigan
Paul Shreve, MD
Medical Director, Department of Radiology
PET Medical Imaging Center and Spectrum Health
Grand Rapids, Michigan
Barry L. Shulkin, MD, MBA
Chief, Department of Radiologic Sciences
Division of Nuclear Medicine
St. Jude’s Children’s Research Hospital
Memphis, Tennessee
Caroline C. Sigman, PhD
President
CCS Associates
Mountain View, California

Heikki Ukkonen, MD, PhD
Assistant to Chief, Department of Cardiology
Turku, Finland
Annick D. Van den Abbeele, MD
Associate Professor, Department of Radiology
Harvard Medical School
Chief and Founding Director, Department of Radiology
Center for Bioimaging in Oncology

Dana-Farber Cancer Institute
Boston, Massachusetts
Richard L. Wahl, MD
Professor, Department of Radiology and Oncology
Henry N. Wagner Jr Professor of Nuclear Medicine
Director, Division of Nuclear Medicine and PET
Vice Chairman for Technology and New Business Development
The Russell H. Morgan Department of Radiology and
Radiological Sciences
The Johns Hopkins University School of Medicine
Baltimore, Maryland


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Contributing Authors

Wolfgang A. Weber, MD
Professor and Director, Department of Nuclear Medicine
University of Freiburg
Freiburg, Germany.
Hans-Jürgen Wester, MD
Department of Nuclear Medicine
Technische Universität München

München, Germany

Jinsong Xia, MD, PhD
Postdoctoral Fellow, Department of Radiology
Division of Nuclear Medicine
The Johns Hopkins Medical Institutions
Baltimore, Maryland
Keiichiro Yoshinaga, MD, PhD
Associate Professor, Department of Molecular Imaging
Hokkaido University Graduate School of Medicine
Sapporo, Japan

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P R E FAC E

n the 6 years since the first edition of this comprehensive
multiauthored textbook on PET was published, there has
been remarkable progress. Progress has been sufficiently
transformative that the title of the textbook has been changed to
Principles and Practice of PET and PET/CT. This title change is
reflective of the major alteration in practice patterns and technology for PET imaging since the introduction of commercial
PET/CT systems around the turn of the century. The updated text
includes many PET/CT images as well as new chapters specifically
dealing with CT scanning and strategies to optimally integrate CT
and PET to a “one-stop” diagnosis for cancer, heart disease, and
other conditions.
In 1993, Chuck Meyer, my colleagues, and I described the
fusion of PET metabolic images with high-quality CT or MRI using
software as “Anatomolecular Imaging.” While clearly useful, the
fusion approach was not routinely practiced because it was time
consuming and not uniformly reliable for non-CNS applications.
Routine whole-body PET/CT fusion was not the norm in practice
until the introduction of dedicated hardware approaches leading to
the current “in line” PET/CT, by the instrumentation group at the
University of Pittsburgh led by David Townsend. The important
contributions of the late Dr. Bruce Hasegawa to SPECT/CT and
coincidence PET/CT fusion imaging must be recognized as well.
PET/CT technology changed the PET world in the course of only a
few years. At present, essentially every new PET scanner is a PET/CT
scanner with improved performance of PET/CT as compared to
PET in nearly all clinical settings in body imaging.

It is very gratifying to have the opportunity to observe and participate in such a transformative technology. I recall vividly observing the coincidence detecting probes and early PET scanners when
I was a student and then a resident/fellow at Washington University
School of Medicine in St. Louis, from the mid-1970s to the early
1980s. Drs. Ter-Pogossian and Siegel attempted to teach me the
value of the PET method. At that time, I had only a limited concept
of the vast potential of noninvasively imaging many aspects of
human biology in all organ systems, repeatedly, quantitatively, and
nondestructively.

I

Some of the vast potential of PET has been transformed to
practice as PET/CT, now performed on several million patients
per year worldwide. PET/CT technology is clearly here to stay.
But in the next several years, it is anticipated that more changes
are in store. PET/MRI has been developed and is in early stages of
deployment. Further, increased scrutiny of radiation doses from
CT and nuclear methods, as well as uncertainty regarding and the
need for intravenous contrast must be kept in mind, given concerns regarding radiation, carcinogenesis, and renal toxicity.
Dedicated PET imaging of small body areas or with positronsensitive probes and imaging systems, PET-guided biopsies, and
more sophisticated quantitation will likely evolve as important.
Rapid readout of treatment response to adapt the therapies is
expected to have a major role in cancer treatments. New PET
tracers, many discussed in this text, will be applied more broadly
in research and clinical practice. The realities of health care
expenses and real limitations in the resources society can devote
to health care spending may be greater limitations than the technologies we can develop.
I am confident the readers will find this text a valuable resource.
My co-authors and I have tried to provide a comprehensive, but not
exhaustive, clinically focused text that presents sufficiently detailed

basic science information for understanding the key aspects of the
major clinical and research applications of PET and PET/CT. I would
particularly like to thank Dr. Rob Beanlands, who served as the Associate Editor on the updated section on cardiac PET and PET/CT
imaging. The efforts of Julia W. Buchanan in providing thoughtful
editing of many of the chapters are also greatly appreciated. In addition, the support and encouragement of Kerry Barrett of Lippincott
Williams & Wilkins was essential to completing this comprehensive
text.
Hopefully, you will keep this book near your PET/CT reading
workstation and refer to it often in the coming years. It should, like
the first edition, serve as a useful starting point and reference tool
for your clinical or research work.
Richard L. Wahl, MD

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P R E FAC E TO T H E F I R S T E D I T I O N

ur purpose in writing this book is to present a comprehensive guide to how positron emission tomography (PET)
works, but more critically, how to use PET to enhance the
care of patients. The basic principles of the technique are presented
first and discuss how PET radionuclides are produced and incorporated into useful compounds to measure a specific molecular
process in vivo. Once in the human body, these compounds are
detected with specialized and ever-evolving equipment, such as
PET/CT scanners. Quantification of PET data requires sophisticated processing of the data sets to produce the displayed images.
While much of the focus of the book is clinical, research applications of PET across a wide range of organ systems are also presented.
For nearly 20 years, PET was a potent research tool, but it was
available only at select academic institutions. Large teams of investigators from diverse disciplines were needed to handle the complexities involved in the production of short-lived isotopes with
balky cyclotrons, the performance of rapid radiochemistry to generate suitable human tracers, and to produce and analyze the often
“fuzzy” images resulting from these efforts. Several scans a week
represented a “busy” PET operation. The possibility that the “complex” PET technique could become a routine diagnostic method
throughout the world by the turn of the century seemed exceedingly unlikely in the late 1970s and early 1980s. However, through
the persistence of many investigators and advances in computer
technology, cyclotrons, and chemistry are now computer-controlled and substantially automated. Instead of an entire floor of
computers that was required to process images, now a single small
console sitting on a desk does the task. A single outpatient PET
scanner can now perform 10 to 20 scans per day, and scanners are
becoming faster.
In the late 1980s, it became apparent that the PET technique
and 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) had huge clinical
potential. Pilot studies in animals and humans showed FDG PET’s
ability to image lung, breast, and other cancers—in addition to its
known ability to image function in the brain and heart. By the mid

1990s, it became clear to those working with PET that it was clinically effective, but its dissemination was delayed largely due to concerns about health care costs and the prevailing enthusiasm for CT
and magnetic resonance imaging (MRI) at that time. Compelling
scientific data, reimbursement for PET, involvement of large medical equipment manufacturers in PET, and acceptance of PET by

O

referring physicians due to the excellent clinical results have moved
the field rapidly forward in the last few years.
Nearly 5 years before the publication of this book, we felt there
was a very large gap in the PET literature and saw a critical need for
a textbook that would provide a comprehensive guide to the rapidly
evolving field of PET, from the fundamental physics and chemistry,
to details on how to implement and interpret clinical PET images.
PET is used to study most organ systems of the body and has
contributed to our understanding of the basic physiology and
pathophysiology of oncological disorders, the brain, the heart, and
other organ systems. PET is also playing a major role in the development of new stable (nonradioactive) drugs and is an ideal tool to
image phenotypic alterations resulting from the altered genotype.
To date, the greatest application of PET in routine clinical studies
has been in patients with cancer, where PET images functional
alterations caused by molecular changes in contrast to the traditional anatomic methods of imaging cancer like CT.
The increased metabolism of malignant cells makes it possible
to image a wide variety of tumors with the glucose analog, FDG. In
this book we have chosen authors who have made major contributions in establishing FDG PET as an accurate, sensitive, and useful
technique for evaluating and monitoring patients with numerous
types of cancer. The validation of the clinical findings, combined
with the current speed at which a study, can be completed and the
fact that third-party payers will now provide reimbursement for
many studies, has made FDG PET a modality that medical centers
cannot be without. The recent addition of PET/CT is further

adding to the refinement of these studies by combining precise
fusion of anatomic information with the molecular image data as
“anatomolecular” images. Referring physicians can quickly relate to
images that fuse form and function, and they now routinely wish to
have PET or PET/CT to enhance the care for their patients. A variety of other PET radiotracers are discussed, which will further
expand the use of clinical PET beyond FDG.
At present, PET is the most rapidly growing area of medical imaging because of its considerable power, and it has now reached a new
plateau of widespread, worldwide distribution. We hope this book,
which reviews all aspects of PET, will serve as a useful starting point
and reference tool to all who use PET in their clinical or research work.
Richard L. Wahl
Julia W. Buchanan

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PRINCIPLES AND PRACTICE
OF PET AND PET/CT
SECOND EDITION


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CHAPTER

1

Production of Radionuclides
for PET
RONALD D. FINN AND DAVID J. SCHLYER

PRODUCTION
Definition of Nuclear Reaction Cross Section
Enriched Targets

TARGETS AND IRRADIATION
Traditional PET Radioisotopes
Target Irradiation
Specific Activity
Fluorine-18
Carbon-11

oupled with the advancement in noninvasive cross-sectional
imaging techniques to identify structural alterations in
diseased tissues, there have been significant advances in
the development of in vivo methods to quantify functional metabolism in both normal and diseased tissues. Positron emission
tomography (PET) is an imaging modality that yields physiologic
information necessary for clinical diagnoses based on altered tissue metabolism.
One of the most widely recognized advantages of PET is the use
of the positron-emitting biologic radiotracers (carbon-11 [11C], oxygen-15 [15O], nitrogen-13 [13N], and fluorine-18 [18F]) that mimic
natural substrates. These radionuclides have well-documented
nuclear reaction cross sections appropriate for “baby” cyclotron energies, and the corresponding “hot atom” target chemistries are reasonably well understood. A disadvantage these biologic radionuclides
possess is their relatively short half-lives, which means they cannot be
transported to sites at great distances from the production facility.
Currently, there are four PET drugs officially recognized by the
U.S. Food and Drug Administration (FDA) and approved for intravenous injection. They are sodium fluoride (18F) (previously FDA
approved and currently United States Pharmacopeia [USP] listed),
rubidium-82-chloride (82Rb), 13N-ammonia and fluorodeoxyglucose (18F-FDG). In 1972, 18F (New Drug Application [NDA] 17-042)
was approved as an NDA for bone imaging to define areas of altered
osteogenic activity, but the manufacturer ceased marketing this
product in 1975. Rubidium-82-chloride (NDA 19-414) was
approved in 1989 and is indicated for assessment of regional
myocardial perfusion in the diagnosis and localization of myocardial
infarction. Most recently, 18F-FDG (NDA 20-306) was recognized in
1994 for identification of regions of abnormal glucose metabolism

initially associated with foci of epileptic seizures, but it is now mostly
used and approved for its application to various primary and
metastatic malignant diseases (1). Nitrogen-13-ammonia is approved
for assessment of myocardial blood flow.
Over the past few decades, PET studies with radiolabeled drugs
have provided new information on drug uptake, biodistribution,
and various kinetic relationships. A critique on the design and

C

Nitrogen-13
Oxygen-15
Novel Solid Targets for PET Radiopharmaceutical
Preparation
Generator-Produced Positron-Emitting Radionuclides
Radionuclide Generator Equations
SUMMARY
ACKNOWLEDGMENTS

development of PET radiopharmaceuticals has been published (2),
as well as several articles involving the future of PET in drug
research and development and the production targetry available
from various manufacturers of cyclotrons (3). Growth in clinical
PET applications has led to increased interest in and demand for
new PET radiopharmaceuticals.

PRODUCTION
Definition of Nuclear Reaction Cross Section
A nuclear reaction is one in which a nuclear particle is absorbed
into a target nucleus, resulting in a very short-lived compound

nucleus. This excited nucleus will decompose along several pathways and produce various products. A wide variety of nuclear reactions are used in an accelerator to produce artificial radioactivity.
The bombarding particles are usually protons, deuterons, or helium
particles. The energies used range from a few million electron volts
to hundreds of million electron volts. One of the most useful models for nuclear reactions is the compound nucleus model originally
introduced by Bohr in 1936. In this model, the incident particle is
absorbed into the nucleus of the target material and the energy is
distributed throughout the compound nucleus. In essence, the
nucleus comes to some form of equilibrium before decomposing
and then emitting particles. These two steps are considered to be
independent of each other. Regardless of how the compound
nucleus got to the high-energy state, the decay of the radionuclide
will be independent of the way in which it was formed. The total
amount of excitation energy contained in the nucleus will be given
by the following equation:
Uϭ

MA
MA ϩ Ma

Ta ϩ Sa

where U equals excitation energy, MA equals the mass of the target
nucleus, Ma equals the mass of the incident particle, Ta equals
kinetic energy of the incident particle, and Sa equals the binding

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2

Principles and Practice of PET and PET/CT

FIGURE 1.1. Formation and disintegration of the
compound nucleus.

energy of the incident particle in the compound nucleus. The
nucleus can decompose along several channels, as shown in Fig. 1.1.
When the compound nucleus decomposes, the kinetic energy
of all the products may be either greater or less than the total kinetic
energy of all the reactants. If the energy of the products is greater,
the reaction is said to be exoergic. If the kinetic energy of the products is less than that of the reactants, the reaction is said to be endoergic. The magnitude of this difference is called the Q value. If the
reaction is exoergic, Q values are positive. An energy-level diagram
of a typical reaction is shown in Fig. 1.2.
The nuclear reaction cross section represents the total probability that a compound nucleus will be formed and that it will decompose in a particular channel. There is a minimum energy below
which a nuclear reaction will not occur except by tunneling effects.
The incident particle energy must be sufficient to overcome the
coulomb barrier and to overcome a negative Q value of the reaction. Particles with energies below this barrier have a very low probability of reacting. The energy required to induce a nuclear reaction
increases as the Z of the target material increases. For many low-Z

materials it is possible to use a low-energy accelerator, but for
high-Z materials it is necessary to increase the particle energy (4).
The following relationship (4) gives the number of reactions
occurring in 1 second:
dn ϭ I0 NAdssab
where dn is the number of reactions occurring in 1 second, I0 is the
number of particles incident on the target in 1 second, NA is the
number of target nuclei per gram, ds is the thickness of the material
in grams per centimeter squared, and ␴ab is the parameter called the

cross section expressed in units of centimeters squared. In practical
applications, the thickness ds of the material can be represented by
a slab of thickness ⌬s thin enough that the cross section can be considered as constant. NA ds are then the number of target atoms in a
1-cm2 area of thickness ⌬s. If the target material is a compound,
rather than a pure element, then the number of nuclei per unit area
is given by the following expression:
NA ϭ

FIGURE 1.2. Energy level diagram for a nuclear reaction. The Q value
is the difference in the energy levels of the reactants and the products.

FACᑣ
AA

where NA is the number of target nuclei per gram, FA is the fractional isotopic abundance, C is the concentration in weight, ᑣ is
the Avogadro number, and AA is the atomic mass number of
nucleus A.
This leads to one of the basic facts of life in radioisotope production. It is not always possible to eliminate the radionuclidic
impurities even with the highest isotopic enrichment and the
widest energy selection. An example of this is given in Fig. 1.3 for
the production of iodine-123 (123I) with a minimum of iodine-124
(124I) impurity (5–8).
As can be seen from Fig. 1.3, it is not possible to eliminate the
124
I impurity completely during the 123I production since the 124I is
being concurrently formed at the same energy. To minimize the 124I
impurity, irradiation of the target at an energy where the production of 124I is near a minimum becomes an option. In this case a
proton energy higher than 20 MeV will give a minimum of 124I
impurity.

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Chapter 1 • Production of Radionuclides for PET

3

With energy constraints imposed by the various accelerators
chosen for installation in imaging facilities, the availability and the
application of stable enriched target materials for the production of
the biologically equivalent radionuclides is of paramount concern.
The calutrons at Oak Ridge National Laboratory are no longer in
service to prepare and provide the numerous stable enriched
nuclides needed for the variety of radionuclides being evaluated for
clinical applications. These concerns still plague many investigators
who have experienced the lack of or shortages in availability of such
important target materials. A current example involves H218O for
18
F production. The H218O target is the choice of most centers for
the production of 18F-labeled fluoride anion used in most 18Flabeled radiopharmaceutical production (12,13). Fortunately, other
sources have come forward to provide the H218O target as use of
18
F has increased.

TARGETS AND IRRADIATION
Traditional PET Radioisotopes
FIGURE 1.3. Plot of yield from the 124Te(p,n)124I and the 124Te(p,2n)123I
nuclear reactions as a function of energy on target.

Enriched Targets

Although they generally play a supplementary role to the applications
in the production of radionuclides, stable isotopically labeled compounds find widespread use in pharmacologic and toxicologic investigations. Their use as internal standards in such sensitive and specific
analytical techniques as gas chromatography-mass spectroscopy and
high-pressure liquid chromatography coupled with mass spectroscopy is of great benefit in the assay of body fluids. Paramagnetic
stable nuclides such as carbon-13 (13C) offer opportunities for
nuclear magnetic resonance (NMR) analyses of biological samples
and possibly whole-body NMR in metabolic studies (9–11).
Stable isotopes have for many years been the foundation for the
production of radionuclides when pure radionuclides are necessary. Since the invention of the “cyclotron” by Professor E.O.
Lawrence in 1929 and proof of acceleration by M.S. Livingston in
1931, the accelerators have provided unique radionuclides for
numerous applications.
In the past decade there has been a significant increase in the
acquisition and use of “small” cyclotrons devoted principally to
operation by chemists for the production of the biomedically useful
radiolabeled compounds or radiopharmaceuticals. The primary
impetus has been the acceptance of the potential of PET as a
dynamic molecular imaging technique applicable to clinical diagnoses while providing the opportunity to evaluate novel radiotracers and radioligands for monitoring in vivo biochemical or physiologic processes with exquisite sensitivity.
Concurrent with the growth of PET/cyclotron facilities has
been an emphasis on the production of larger amounts of the
short-lived radionuclides in a chemical form suitable for efficient
synthetic application. The radionuclidic purity of the final nuclide
is an important concern. Targetry and target chemistry continue to
be factors for the synthetic chemist’s consideration and appreciation of material science and radiation chemistry effects.

There are four positron-emitting radioisotopes that are considered
the biologic tracers and their clinical and investigational uses are
extensive. The radionuclides are 18F, 11C, 13N, and 15O. The reason
these are so commonly used is that they can be easily substituted
directly onto biomolecules. Carbon-11, 13N, and 15O are the “elements of life.” Substitution of 11C for carbon-12 (12C) does not significantly alter the reaction time or mechanisms of a molecule. A

similar situation exists for 13N and 15O. Fluorine-18 can often be
substituted for a hydroxy group in a molecule or placed in a position where its presence does not significantly alter the biological
behavior of the molecule. When the nucleus decays, the positron
emitted will slow to thermal energies and annihilate upon interaction with an electron to produce two 511 keV gamma rays emitted
at nearly 180 degrees to each other. The decay characteristics of the
positron-emitting radionuclides allow the physiologic processes
occurring in vivo to be quantitated by detectors outside the body.
Physiologic modeling can be carried out using this information,
and quantitative assessments of the biologic function can be made.

Target Irradiation
The positron-emitting radionuclides are produced during the target irradiation and converted to a synthetic precursor, either in the
target or immediately after exiting the target. The precursor is next
converted into the molecule of interest. This chapter covers only the
targetry and the formation in the target of the chemical compound.
The formation of precursors outside the target and the conversion
of these precursors to the desired radiotracer are covered in Chapter
2. Most of the targets for the production of the biologic radionuclides have been either gases or liquids, although several solid targets have also been developed.
The number and type of products that are obtained in a target
are a function of the irradiation conditions, the mixture of gases or
liquids in the target, and the presence of any impurities in the target
or gas mixture. Changing the chemical composition or physical
state of the target during irradiation can alter the chemical form of
the final product (14). These are all results of the “hot atom” chemistry and radiolysis occurring in the target during the irradiation.
Hot atom is the term used to identify atoms with excessive thermal
or kinetic energy or electronic excitation. When an atom undergoes