Molecular Targeting with Radionuclides: State of the Science*

CONTINUING EDUCATION Molecular Targeting with Radionuclides: State of the Science* Scott H. Britz-Cunningham, MD, PhD; and S. James Adelstein, MD, PhD Joint Program in Nuclear Medicine, Harvard Medical School, and Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts foundly, if not unrecognizably, altered in the not-too-distant Inherent in the application of advances in biomedical science to future. nuclear medicine is the concept of molecular targeting: the in vivo concentration of labeled tracer by a gene, its transcribed WHAT IS MOLECULAR TARGETING? DNA, or its protein product. This mechanism of localization has been and is being exploited for both nuclear imaging and ra- “Molecular targeting” may be defined as the specific dioisotopic therapy. Agents, such as antisense molecules, concentration of a diagnostic tracer or therapeutic agent by aptamers, antibodies, and antibody fragments, can be aimed at virtue of its interaction with a molecular species that is molecular targets. Tumor and nerve cell receptors provide such distinctly present or absent in a disease state. The molecular targets. So do certain cellular physiologic activities, including species in question could be a mutated locus of DNA or its metabolism, hypoxia, proliferation, apoptosis, angiogenesis, response to infection, and multiple drug resistance. In this article protein or RNA product; a gene product of normal sequence we review the principles of molecular targeting based on radio- and structure, aberrantly expressed in a given tissue; or a isotopic methods and provide examples from the literature. We transcriptionally normal gene product whose structure or discuss applications to imaging and therapy and point out the function has been modified by abnormal RNA splicing or hurdles that must be overcome in bringing molecular targeting posttranslational processing. Molecular targeting agents dif- to clinical reality. fer from conventional physiologic tracers, such as radioio- Key Words: molecular targets; molecular imaging; radioiso- dide or myocardial and cerebral perfusion indicators, in that topic therapy physiologic tracers are directed toward processes character- J Nucl Med 2003; 44:1945–1961 istic of a normal tissue or cell type and are dependent on the cooperation of multiple gene products or on nonspecific bulk processes, such as diffusion, membrane permeability, or electrostatic interactions. The discovery of techniques for the manipulation of Implicit in the molecular paradigm of disease description nucleic acids, including bacterial DNA restriction systems, is the assumption that diseased or injured cells are different DNA sequencing, reverse transcription, and polymerase from their normal neighbors—specifically, that they dem- chain reaction, has catalyzed an explosion of knowledge of onstrate a distinctive “pathotype” or signature pattern of the molecular basis of human disease, with Ͼ93,000 mo- altered expression or processing of gene products. This lecular biology-related Medline citations appearing during pattern would be common to cells of similar origin if the year 2001 alone (authors’ informal count). Equipped subjected to the same disease process. Thus, even cells with this new understanding, 21st Century medicine is subjected to passive injury, such as trauma, ischemia, or poised to implement a new class of therapeutics, based on bacterial invasion, will respond by upregulating response detailed models of the processes of disease, with exquisite elements, such as heat-shock proteins, interferons, or hy- specificity worthy of Ehrlich’s notion of the “magic bullet.” poxia-inducible factor, or, when adaptation fails, by activat- While every branch of medicine is likely to undergo even- ing caspases and other apoptotic factors during the final tual transformation by this revolution, nuclear medicine has throes of cell death. Characterization of such pathotypes up already begun to feel its effects and is likely to be pro- till now has relied on painstaking hit-or-miss methods of analyzing one gene product at a time but recently has been Received Apr. 7, 2003; revision accepted Sep. 25, 2003. accelerated by the introduction of genomic and proteomic For correspondence or reprints contact: Scott H. Britz-Cunningham, MD, methods of mass screening. PhD, Division of Nuclear Medicine, Department of Radiology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. As the most sensitive noninvasive modality presently E-mail: [email protected] available for the detection and mapping of pathotypic mark- *NOTE: FOR CE CREDIT, YOU CAN ACCESS THIS ACTIVITY THROUGH THE SNM WEB SITE (http://www.snm.org/education/ce_online.html) ers, nuclear medicine enjoys a strategic position at the THROUGH DECEMBER 2004. forefront of this trend. As will be seen below, many of these MOLECULAR TARGETING • Britz-Cunningham and Adelstein 1945 markers or their natural ligands can be more or less directly affinity and to the density and geometry of available translated into potential imaging agents. These agents can epitopes. be used to establish a primary diagnosis; to guide therapy by In the transporter–substrate mode, the signal molecule is demonstrating the presence of appropriate molecular tar- concentrated within a cell or tissue compartment via a gets; to confirm delivery of gene therapy agents; to assess mechanism in which the activity of the target molecule is response after therapy; and to evaluate new therapeutic the rate-limiting factor. Although the signal molecule may compounds. Many agents, labeled with cytocidal ␤-or be trapped in the compartment by subsequent modification, ␣-emitting radionuclides instead of ␥-emitters, will also be this modification is not rate-limiting, and the transporter suitable for targeted radiotherapy. itself does not chemically alter the substrate. The transporter In this article, we will review the possibilities for molec- may have multiple substrates (e.g., both glucose and other ular targeting and include discussions of how molecular hexoses); however, the signal molecule must have a re- imaging and targeted radionuclide therapy work, what clin- stricted interaction with a single transporter. Since many ical applications are now available, what new agents are transporters have multiple isoforms, this can be effectively under development, what frontiers remain, and, finally, dependent on context. Furthermore, the transporter must be what fundamental limits to molecular targeting are likely to uniquely present or absent in a process of disease. Thus, be encountered. The focus will be primarily on radioiso- FDG can be considered a molecular targeting agent for topic methods, as opposed to MRI agents or optical-fluo- Glut-1 transporters in bronchogenic carcinoma or in ische- rescence approaches, since these are likely to have the most mic myocardium, because Glut-1 is not expressed at equiv- general clinical application in the near term. Reviews of alent levels in healthy lung or heart. In the context of hepatobiliary imaging, however, diisopropyl iminodiacetic alternative methods are presented elsewhere (1–3). acid would not be considered a molecular targeting agent because the anionic-binding carrier protein that is responsi- HOW DOES MOLECULAR IMAGING WORK? ble for its uptake into hepatocytes is expressed both in As with other imaging applications, molecular imaging healthy people and in patients with cholecystitis, and diag- requires fixation of a signal-emitting molecule (e.g., one nosis is based on the pattern of bulk flow of excreted tracer. containing a radioactive, fluorescent, or paramagnetic label) In the enzyme–substrate model, the target molecule is an within the cell or tissue where the target is expressed. There enzyme that chemically modifies the signal molecule, fixing are several different mechanisms by which this can be its biodistribution. Unlike receptor–ligand binding, there is no fixed stoichiometry. A single molecule of enzyme can brought about. In the receptor–ligand model, one signal interact with many substrate molecules, multiplying the molecule (the ligand) binds with high affinity to a specific signal manyfold. A very rare target can be detected, pro- site on a target molecule (the receptor), which has a station- vided that it has a high turnover (k ) and a high affinity ary biodistribution over the period of imaging. If multiple cat (low K ) for the signal molecule as a substrate. A key issue binding sites are present, a single receptor can bind more m in enzyme targeting is physical delivery of the substrate. than one ligand; however, the maximum stoichiometry will Some enzymes, such as matrix metalloproteinases, are ex- always be a low multiple of the number of receptor mole- tracellular in location. Many desirable targets, however, are cules available. The key determinants of success for this restricted to specific intracellular compartments, where ac- type of imaging are the specificity and affinity of the recep- cess to substrates is tightly controlled. This is quite different tor–ligand interaction, as well as the receptor density itself. from the case of receptors, many of which are accessible at The receptor–ligand pair does not necessarily have to mimic the cell membrane. Thus, an effective target molecule either a naturally occurring interaction. For example, peptides must be capable of rapid diffusion into the cell or must use derived artificially from phage display can bind their targets a transport mechanism with high throughput characteristics. with affinities equal

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