ABSTRACT
I. Introduction 415
II. Molecular Imaging Assays 417
III. Imaging Targets, Probes, Processes, and Applications 419
A. Imaging Glycolytic Activity 419
B. Imaging Bone Metastases with 18F-Fluoride 421
C. Imaging Amino Acid Metabolism 422
D. Imaging Cell Membrane Synthesis 424
E. Imaging Tumor Cell Proliferation 426
IV. Using Analogs of Therapeutic Drugs as Imaging Probes 429
V. Imaging Tyrosine Kinase Receptor Densities 430
VI. Imaging the Distribution of Radiolabeled
Chemotherapeutic Agents 431
VII. Imaging of the avb3 Integrin 432
VIII. Summary 434
References 434
I. Introduction
In 1906, Flexner and Jobling (1) established a tumor model by transplanting
a spontaneously growing rat tumor into generations of rats. One of the
tumor-bearing rats was shipped to Berlin where Warburg et al. (2) conducted
their landmark studies on glucose metabolism of tumors, which revealed that the
metabolism of tumors is predominantly one of anaerobic glycolysis. Thirty to
forty years later, in the 1950s and 1960s, Sokoloff et al. (3) labeled deoxyglucose
with carbon 14, and Reivich subsequently marked deoxyglucose with fluorine 18,
thus providing radiolabeled analogs of glucose that could be used for tumor
imaging. In the 1970s, Phelps et al. (5) built the first positron emission tomogra-
phy (PET) scanner, enabling the translation of the fundamental discoveries by
Warburg et al. (2) into the most innovative and exciting clinical imaging tool
in oncology (6). 18F-fluorodeoxyglucose PET (FDG-PET) and integrated PET/computed
tomography (CT) are now used to diagnose, stage, and restage malignancies
and to monitor treatment effects in patients with cancer. For most cancers,
PET accomplishes these tasks with greater accuracy than conventional anatomic
imaging. Nevertheless, limitations remain. Foremost among these is the nonspe-
cific nature of FDG uptake in patients with cancer. As shown by Warburg et al. in
1924 (2), benign tumors can also exhibit increased rates of glucose metabolism
and, hence, increased FDG uptake. Accumulation of FDG in white blood cells,
macrophages, fibroblasts, and other cells can also result in increased FDG
uptake because inflammatory cells require glucose as their energy substrate.
Thus, FDG-PET imaging provides many but not all of the answers needed for
comprehensive imaging in humans. Some cancers do not exhibit increased
rates of glycolysis and are, therefore, not visible on FDG-PET images. For
these, anatomic imaging remains the most important diagnostic tool. Despite
these limitations, FDG will remain the most important molecular imaging
probe in cancer diagnostics.