Editorial pubs.acs.org/bc
More Chemistry Is Needed for Molecular Imaging
N
delta-opioid receptor was conjugated with near-infrared fluorophores for imaging of lung cancer. In comparison to peptides, synthesis of oligonucleotide and hyaluronic acid conjugates is more chemically challenging, and Virta et al. describe an impressive effort in synthesizing 68Ga-labeled such conjugates for Positron Emission Tomography (PET) imaging in rats, which shows the potential for imaging of mycocardial infarction in rats. Activatable or “smart” probes generate reporting signals when interacting with the target molecules and their creation is extremely rich in chemistry. Such strategies are wellrepresented in this special issue and these new approaches have tremendous advantages for in vivo optical imaging because of the reduction in noise. The cost of these approaches is oftentimes a net reduction in signal such that the signal-tonoise ratios are the key indicator of utility in vivo. The activatable probes reported in this special issue exemplify the “smart” in smart probes and make a noteworthy contribution to the imaging field. Wender et al. describe a biocompatible ruthenium catalyst that can activate alloc-protected aminoluciferin in a cellular environment to free aminoluciferin, a substrate of the luciferase reporter. This reporter gene strategy is ideally suited for imaging in laboratory animals, but further exploration may extend it into pro-drug activation and targeted therapy. By taking advantage of Fe2+-induced N−O cleavage of acylated hydroxylamine, Wang et al. designed a fluorogenic probe for selectively imaging Fe2+. In a structure−activity relationship study, Yang et al. investigated the selectivity of a fluorogenic probe for peroxynitrite over hypochlorite. These new probes will enable imaging of metabolism in vivo. Multimodality and combination probes are enabling more multiplexed imaging assays, and toward this end Lavis et al. modified a fluorescein analog to enable the design of fluorogenic probes with two orthogonal masking groups for sensing dual targets. Most of the activatable agents have optical signatures, but similar strategies are being investigated for other imaging modalities. One excellent example is the smart contrast agent for Magnetic Resonance (MR) imaging of intracellular Ca2+ described by Meade and colleagues where they employed an old trick of masking negatively charged carboxylates with esterase-cleavable groups to enhance the cell permeability of a Ca2+-sensitive MRI contrast agent. There have been significant advances in in vivo labeling approaches and Kele et al. report polarity-sensitive, benzothiazolium-based fluorescent probes that carry azide tags for in vivo “click” labeling of target molecules. Biomolecules can also be engineered to build protein based activatable probes. Kim et al. report on a sandwiched full-length artificial luciferase with two outer proteins of interest to produce a genetically encoded molecular tension probe for in vivo bioluminescence imaging of ligandinduced protein−protein interactions.
oninvasive molecular imaging is becoming an indispensible tool for elucidating biology in animal models of human health and disease, and for diagnosis and guided therapy in the clinic. A key component in enabling this powerful technology is innovation in molecular probe design and novel probe chemistries. Imaging a biological target with specificity and reasonable signal-to-noise requires thoughtful probe designs that take into consideration the imaging modality, the molecular target to be imaged, and all of the requisite in vivo biodistribution and bioavailability issues of a pharmaceutical agent. Over the past decade there have been a tremendous number of new strategies for imaging probe design, and significant advances in the chemistry of molecular probes. This special issue of Bioconjugate Chemistry intends to capture some of latest advances in this field that have changed the way we study biology and diagnose disease. The enthusiastic response from the chemistry and imaging communities to the call for submission produced 22 exceptional articles reporting some exciting advances in molecular probe chemistries, with some dramatic demonstrations of their utility as in vivo imaging agents. We are pleased to present these reports to you and have summarized their significance below. Small molecular probes possess favorable pharmacokinetics due to their small size and chemical tenability, and are attractive as imaging probes. A study by Smith et al. compares the targeting and imaging of three phenoxide-bridged zinc(II)bis(dipicolylamine) fluorescent probes for imaging cell death. In this study they extended this probe to the Single Photon Emission Computed Tomography (SPECT) imaging by examining the bioditribution of an 111In-labeled version with selective cell death targeting ability in a thymus atrophy model, and observed significant accumulation in dead and dying tissue with modest off-target signals in nonclearance organs. McKenna et al. developed a new synthetic method using epichlorohydrin as linker to label heterocyclic bisphosphonates with fluorescent dyes for bone imaging which will have utility for imaging in osteogenic and osteolytic diseases. Schnermann, Kobayashi, and colleagues report a new cyanine-based nearinfrared fluorophore with a high in vivo tumor-to-background ratio through modulating net charge and charge distribution. Peptide ligands have been widely investigated as imaging and therapeutic agents since they are readily chemically synthesized, can be used for proteolytic assays, and are easily labeled. Using a structural model, Wang et al. developed a small peptide specific for the extracelluar domain of HER2 and fluorescently labeled it for molecular endoscopic imaging of colorectal cancer. Because of such advances there has been a dramatic increase in the development of fluorescence-based endoscopic tools that span a range of scales from macro- to microscopic imaging, and multimodality imaging tools comprising wide-field systems and high-resolution microendoscopes are continuing to demand the development of new molecular probes. In another study by Morse et al., synthetic peptide antagonist against the © 2016 American Chemical Society
Special Issue: Molecular Imaging Probe Chemistry Published: February 17, 2016 265
DOI: 10.1021/acs.bioconjchem.6b00056 Bioconjugate Chem. 2016, 27, 265−266
Bioconjugate Chemistry
Editorial
Bioconjugation reactions are basic tools for the synthesis of molecular imaging probes, and this special issue includes a few examples. One approach examined the suitability of the widely used nitrilotriacetate for conjugating phosphorescent Ptporphyrins to nanoparticles functionalized with oligohistidine tagged proteins. In another study the design of tris(hydroxypyridinone) bifunctional chelators is described for rapid labeling with 68Ga for PET imaging. Lewis et al. demonstrated in vivo bioconjugation via the bioorthogonal inverse electron demand Diels−Alder reaction, one of the most rapid bioorthogonal click ligations, for 18F-based pretargeted PET imaging. The review by Perrin, Schirrmacher, and colleagues provides a very comprehensive overview of the status of borate and silicon based 18F-radiolabeling reactions for PET imaging. Remaut et al. thoroughly reviewed bioconjugation strategies for fluorescently labeling polynucleotides such as plasmid DNA and mRNA for live-cell imaging. Nanoparticles have emerged as an important class of molecular imaging probes and possess unique advantages for multimodality molecular imaging. Two studies report exciting advances in the synthesis and evaluation of dual-modality (MR and multispectral photoacoustic imaging) and trimodal (MRI, PET/SPECT and optical) imaging nanoparticles. Scheper and colleagues investigated the effect of methoxy polyethylene glycol groups and their grafting density on the stability and properties of quantum dots. Djanashvili et al. elucidated the fate of surface coating molecules of nanoparticles upon neutron irradiation. The multifunctional nature of these nanoprobes is their strength and they will have utility in a wide variety of preclinical and clinical applications. The exciting studies in this special issue are just a small collection of vast ongoing efforts in the development of molecular imaging probes, and exemplify some of the best work in the field. It is our hope that this fine collection will serve to both inform the community of the ingenuity in the field of molecular probes, and also promote dialogue between the probe producersthe chemistand the probe usersthe biologistand through the excitement generated by this special issue attract the broad chemistry community to research in the field of molecular imaging. We are proud to have been selected to represent our community as editors of this special issue, but are also greatly humbled by the amazing work that this issue represents. We anticipate that this is just one small step toward a future where animal models become “transparent” for scientific investigation such that they can better be used to inform and direct clinical work, and where patients can be imaged with multifunctional molecular probes that better inform their physicians for earlier diagnosis and greater precision in therapy. The many imaging challenges in this field can best be addressed through effective communication among the many disciplines involved in molecular imaging and we hope we have contributed in some small way with this Special Issue.
■
Jianghong Rao, Guest Editor Christopher H. Contag, Guest Editor
AUTHOR INFORMATION
Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
266
DOI: 10.1021/acs.bioconjchem.6b00056 Bioconjugate Chem. 2016, 27, 265−266
