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.

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Peptides and Peptide Hormones for Molecular Imaging and Disease Diagnosis

Targeted molecular imaging techniques have become indispensable tools in modern diagnostics because they provide accurate and specific diagnosis of disease information. Conventional nonspecific contrast agents suffer from low targeting efficiency; thus, the use of molecularly targeted imaging probes is needed depending on different imaging modalities. Although recent technologies have yielded various strategies for designing smart probes, utilization of peptide-based probes has been most successful. Phage display technology and combinatorial peptide chemistry have profoundly impacted the pool of available targeting peptides for the efficient and specific delivery of imaging labels. To date, selected peptides that target a variety of disease-related receptors and biomarkers are in place. These targeting peptides can be coupled with the appropriate imaging moieties or nanoplatforms on demand with the help of sophisticated bioconjugation or radiolabeling techniques. This review article examines the current trends in peptide-based imaging probes developed for in vivo applications. We discuss the advantage of and challenges in developing peptide-based probes and summarize current systems with respect to their unique design strategies and applications.

/pdf/peptide-based-probes-for-targeted-molecular-imaging-1hdjj626p7.pdf

Peptide-Based Probes for Targeted Molecular Imaging

Human cancer cells overexpress many peptide receptors as molecular targets. Radiolabeled peptides that bind with high affinity and specificity to the receptors on tumor cells hold great potential for both diagnostic imaging and targeted radionuclide therapy. The advantage of solid-phase peptide synthesis, the availability of different chelating agents and prosthetic groups and bioconjugation techniques permit the facile preparation of a wide variety of peptide-based targeting molecules with diverse biological and tumor targeting properties. Some of these peptides, including somatostatin, bombesin, vasoactive intestinal peptide, gastrin, neurotensin, exendin and RGD are currently under investigation. It is anticipated that in the near future many of these peptides may find applications in nuclear oncology. This article presents recent developments in the field of small peptides, and their applications in the diagnosis and treatment of cancer.

/pdf/radiolabeled-peptides-valuable-tools-for-the-detection-and-3zt22ucn15.pdf

Radiolabeled peptides: valuable tools for the detection and treatment of cancer.

Nanomaterials provide large surface areas, relativeto their volumes, on which to load functions. One challenge, however, has been to achieve precise control in loading multiple functionalities. Traditional bioconjugation techniques, which randomly target the surface functional groups of nanomaterials, have been found increasingly inadequate for such control, which is a drawback that may substantially slow down or prohibit the translational efforts. In the current study, we evaluated ferritin nanocages as candidate nanoplatforms for multifunctional loading. Ferritin nanocages can be either genetically or chemically modified to impart functionalities to their surfaces, and metal cations can be encapsulated in their interiors by association with metal binding sites. Moreover, different types of ferritin nanocages can be disassembled under acidic condition and reassembled at pH of 7.4, providing a facile way to achieve function hybridization. We were able to use combinations of these unique properties to prod...

Chimeric ferritin nanocages for multiple function loading and multimodal imaging.

Radiopharmaceutical chemistry for positron emission tomography.

Both bombesin (BBN) analogs and cyclic RGD peptides have been suitably radiolabeled for prostate cancer imaging. However, the limited expression of gastrin-releasing peptide receptor (GRPR) and integrin αvβ3 as well as unfavorable in vivo kinetics limited further applications of these imaging agents. We hypothesize that a peptide ligand recognizing both GRPR and integrin will be advantageous because of its dual-receptor–targeting ability. Methods: A BBN-RGD heterodimer was synthesized from bombesin(7–14) and c(RGDyK) through a glutamate linker and then labeled with 18F via the N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) prosthetic group. The receptor-binding characteristics and tumor-targeting efficacy of 18F-FB-BBN-RGD were tested in vitro and in vivo. Results: FB-BBN-RGD had comparable integrin αvβ3-binding affinity with c(RGDyK) and comparable GRPR-binding affinity with BBN(7–14). 18F-FB-BBN-RGD had significantly higher tumor uptake compared with monomeric RGD and monomeric BBN peptide tracer analogs at all time points examined. The PC-3 tumor uptake of 18F-FB-BBN-RGD was inhibited only partially in the presence of an excess amount of unlabeled BBN(7–14) or c(RGDyK) but was blocked completely in the presence of both BBN(7–14) and c(RGDyK). Compared with 18F-FB-BBN and 18F-FB-RGD, 18F-FB-BBN-RGD also had improved pharmacokinetics, resulting in a significantly higher imaging quality. Conclusion: Dual integrin αvβ3 and GRPR recognition showed significantly improved tumor-targeting efficacy and pharmacokinetics compared with 18F-labeled RGD and BBN analogs. The same heterodimeric ligand design may also be applicable to other receptor system combinations and other imaging modalities.

https://jnm.snmjournals.org/content/jnumed/49/3/453.full.pdf

18F-Labeled BBN-RGD Heterodimer for Prostate Cancer Imaging

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive loss of neurotransmitters, as well as acetylcholinesterase and nicotinic acetylcholine receptors in the central nervous system that leads to learning and memory deficits, among other problems. The disease is associated with increased production and accumulation extracellular amyloid plaques and neurofibrillary tangles in aging human brain, shown in postmortem exams. New methods for reliable in vivo measurement of brain therefore would be much more ideal. PET and SPECT imaging are sensitive methods for the quantitation of AD biomarkers. The development of molecular imaging agents for AD is critically important in the early diagnosis, neuropathogenesis studies and treatment of AD. A number of potential diagnostic PET and SPECT imaging agents targeting AD have been synthesized and evaluated. Although many agents showed excellent results for in vitro monitoring of the disease, there are only several radioligands with high selectivity and specificity to binding sites and appropriate pharmacokinetics, such as [11C]MP4A, [11C]PMP, [11C]nicotine, 2- or 6-[18F]fluoro-A-85380, [11C]SB-13, [11C]PIB, and [18F]FDDNP, that have been tested in AD patients. Here we review some recent progress and development of AD imaging agents using PET and SPECT in human clinical studies.

Development of Alzheimer's disease imaging agents for clinical studies.

Identification and pharmacological characterization of two new selective δ-opioid receptor antagonists, derived from the Dmt-Tic pharmacophore, of potential utility in positron emission tomography (PET) imaging are described. On the basis of its high δ selectivity, H-Dmt-Tic-ϵ-Lys(Z)-OH (reference compound 1) is a useful starting point for the synthesis of 18F-labeled compounds prepared by the coupling of N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) with Boc-Dmt-Tic-ϵ-Lys(Z)-OH under slightly basic conditions at 37 °C for 15 min, deprotection with TFA, and HPLC purification. The total synthesis time was 120 min, and the decay-corrected radiochemical yield of [18F]-1 was about 25–30% (n = 5) starting from [18F]SFB (n = 5) with an effective specific activity about 46 GBq/µmol. In vitro autoradiography studies showed prominent uptake of [18F]-1 in the striatum and cortex with significant blocking by 1 and UFP-501 (selective δ-opioid receptor antagonist), suggesting high specific binding of [18F]-1 to δ-op...

Synthesis of a potent and selective 18F-labeled δ-opioid receptor antagonist derived from the Dmt-Tic pharmacophore for positron emission tomography imaging

Eun Kyoung Ryu

Papers

18F-Labeled BBN-RGD Heterodimer for Prostate Cancer Imaging

Development of Alzheimer's disease imaging agents for clinical studies.

Synthesis of a potent and selective 18F-labeled δ-opioid receptor antagonist derived from the Dmt-Tic pharmacophore for positron emission tomography imaging