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.