Peptides and Peptide Hormones for Molecular Imaging and Disease Diagnosis

Molecular imaging techniques are now indispensable tools in modern diagnostics, because they are highly specific and can provide biological information at the molecular level in living systems.1,2 They have enabled visualization of some of the specific molecular events that play key roles in disease processes, and they have enabled earlier diagnosis, as well as monitoring of therapeutic responses. Various imaging modalities, including positron emission tomography (PET), single photon emission computed tomography (SPECT), optical fluorescence imaging, magnetic resonance imaging (MRI), computed tomography, and ultrasound imaging are all successfully employed in the field of molecular imaging. Specific imaging is generally created by contrast agents; however, most current clinical imaging remains at the anatomical and macro functional level, due to the low targeting efficiency of such agents. To support the unmet needs for in vivo clinical molecular imaging, there has been considerable interest in investigating the design of highly sensitive and specific molecularly-targeted imaging probes. To date, a large variety of sophisticated imaging probes have been developed by combining various imaging moieties (i.e., radioisotopes, fluorophores, and nanoparticles) and targeting ligands (i.e., small molecules, peptides, proteins, antibodies, as well as cells). These efforts have profoundly impacted the availability of imaging probes and significantly improved the performance of imaging modalities. Several review articles have discussed recent development and applications of molecular imaging probes2-7, particularly the utilization of peptide- and peptide hormone-based imaging probes. An ideal imaging probe would have high affinity and specificity for the target of interest. However, requirements beyond targeting selectivity become determinants for the suitability of probes for in vivo applications, including in vivo metabolic stability, high target-to-background ratio, rapid clearance from non-target tissues, and safety. Furthermore, tolerance and flexibility towards bulky chemical modification are also needed, because imaging probes are often associated with labeling of radioisotopes, fluorophores, and materials such as linkers, polymers, and metals. From a practical standpoint, synthetic peptides have attracted much attention as molecular imaging probes for small molecules and macromolecules.8-10 Recent advances in phage display technology, combinatorial peptide chemistry, and biology have led to the development of robust strategies for the design of peptides as drugs and biological tools, resulting in identification of a rich variety library of bioactive peptide ligands and substrates.11-13 To date, peptides that target a number of disease-related receptors, biomarkers, and the processes of angiogenesis and apoptosis are in place. These peptides reveal high specificity for their target at nanomolar concentrations and have low toxicity. They can be easily synthesized, modified to optimize their binding affinity, and possibly further modified structurally to improve their stability against proteolytic degradation, to increase half-life in circulation, and to enhance capillary permeability. All of these attributes promote penetration into tissue and more effective targeting. Furthermore, established peptide synthesis processes are easy to scale up, and they yield reproducible products with well-defined structures. With the combination of advanced imaging sciences, peptide chemistry, and the increasing availability of animal imaging instruments, various kinds of highly specific peptide-based imaging probes for different imaging modalities have been designed and validated in preclinical and clinical investigations. In the following review, an overview of molecular imaging probes associated with peptides and peptide hormones designed for in vivo applications, including those for nuclear imaging, optical imaging, and MRI, is provided. For the sake of focus, this article will not discuss imaging probes that have been tested only under in vitro cellular conditions, although many of these can be applied in vivo. Key peptides for selective targeting of biological receptors or biomarkers and modification strategies for these peptides will be summarized. Then, the unique concepts, characteristics, and applications of various peptide-based imaging probes will be discussed for each of several modalities.