Beyond the Genome: Molecular Imaging in Vivo with PET and SPECT

Abstract

A new era of discovery and medical advances began on June 26, 2000, with the completion of the first map of the human genome (1). Although much work remains to complete a refined map of the human genome, this accomplishment is expected to lead to new medical treatments, drugs, and, ultimately, cures previously thought impossible. In this emerging “postgenomic era,” wherein functionality will be added to this vast array of genetic information, opportunity exists for imaging to play a substantial role in both basic and translational research as related to functional genomics. The overall focus of this article is on functional genomics by means of molecular imaging. Molecular imaging is broadly defined as the characterization and measurement of biologic processes in living animals, model systems, and humans at the cellular and molecular level by using remote imaging detectors. As the new charter for the Society of Molecular Imaging states, the goal of molecular imaging is to advance our understanding of biology and medicine by means of noninvasive in vivo investigation of cellular and molecular events involved in normal and pathologic processes. The focus of molecular imaging is on monitoring gene expression in vivo. The target genes can be either endogenous or exogenous. To meet the goal of monitoring endogenous genes in vivo, a strategic choice must be made regarding whether it is best to image DNA per se, messenger RNA (mRNA transcripts), the protein product of gene expression, or functional activity of the expressed protein. The best strategy may depend on the biochemical context of the target gene under investigation and the desired end point of each experiment. Similarly, to monitor exogenous gene expression in vivo, the choice of measuring DNA, mRNA, protein, or function is fundamental for designing optimal imaging strategies and probes. Ultimately, these choices will be influenced by the characteristics of the biologic pathways and their potential as imaging targets in vivo. One consideration relates to the number of target molecules and their effect on the generation of a sufficient signal-to-noise ratio. For example, direct imaging of DNA would necessitate the imaging of just two molecules per cell, a considerable challenge for remote imaging devices (eg, positron emission tomography [PET], single photon emission computed tomography [SPECT], magnetic resonance [MR] imaging, optical imaging). Furthermore, any two DNA molecules may not be identical (heterologous polymorphisms). Nonspecific and nontarget binding of imaging probes are likely to overwhelm specific signals arising from target DNA. Similarly, mRNA is typically present at only 50 to thousands of molecules per cell; again, direct imaging approaches that necessitate one-to-one correlation with the target molecules face considerable challenges. Conversely, proteins can be present at substantially higher levels, perhaps thousands to millions of copies per cell, and, thus, direct imaging of proteins is achieved readily. Indeed, direct molecular imaging of subtypes of receptor proteins with radiopharmaceuticals is already a laboratory and clinical reality (eg, somatostatin receptor type 2 [SSR-2] imaging with indium-111 DTPA-octreotide or GPIIb/IIIa receptor imaging with technetium-99m-p748) (2,3). Finally, imaging protein function has the potential for massive signal amplification when the target protein is, for example, an enzyme that can magnify the signal by means of metabolic conversion of a precursor substrate or by trapping a Acad Radiol 2001; 8:4–14