Editorial: The Chemistry of Imaging Probes

Molecular imaging consists of the “in vivo characterization and measurement of biologic processes at the cellular and molecular level”. Any molecular imaging procedure requires an imaging probe that is an agent used to visualize, characterize and quantify biological processes in living systems and is specific for a given molecular event. Therefore, chemistry plays a vital role in the development of this cutting-edge methodology. This Research Topic aims at showing how chemistry can offer molecular imaging the opportunity to express all its potential. In fact, the most challenging problems of molecular imaging can be addressed by exploiting the outstanding possibilities offered by modern synthetic organic and coordination chemistry and the efficient procedures provided by conjugation chemistry. 
The optimization of innovative imaging probes can be pursued through different approaches: from the design of imaging units endowed with enhanced sensitivity to the control of the structural and electronic determinants responsible for the molecular recognition of the target molecule. 
A molecular imaging probe typically consists of an agent that usually produces signal for imaging purpose (often made of a metal complex), a targeting moiety, and a linker connecting the targeting moiety and the signaling agent. Currently, the diagnostic imaging modalities include Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Ultrasound (US), Nuclear Imaging (PET, SPECT) and Photoacoustic Imaging (PAI). 
The basis for designing imaging probes for a given application is dictated by the chosen imaging modality, which in turn is dependent upon the concentration and localization profile (vascular, extracellular matrix, cell membrane, intracellular, near or at the cell nucleus) of the target molecule. The development of high-affinity ligands and their conjugation to the targeting vector is one of the key-steps for pursuing efficient molecular imaging probes. 
Importantly, in case of metal-based imaging reporters, the observation of toxic effects related to fast release of the metal ion from the corresponding complex prompted research efforts aimed at the enhancement of both the thermodynamic and kinetic stability of the chelates, via the fine tuning of the physico-chemical properties characterizing the chelating agents. 
We encourage papers focused on the design and synthesis of innovative imaging probes for any imaging modality, on the study on toxicity and stability of the metal-based probes and on in vitro and in vivo testing of new imaging probes for application in oncology, inflammation infection, cardio imaging, neuroinflammation and neuro-oncology.


The Chemistry of Imaging Probes
Over the past decades, the field of molecular imaging (MI) has been rapidly growing involving multiple disciplines such as medicine, biology, chemistry, pharmacology and biomedical engineering. An in vivo MI protocol non-invasively provides visual and quantitative information on normal or pathological processes at the cellular or sub-cellular level. Currently, molecular imaging can be performed in the clinical environment via Magnetic Resonance Imaging (MRI), Optical Imaging (OI), Positron Emission Tomography (PET), Single-Photon Emission Computed Tomography (SPECT), Computed Tomography (CT) and Ultrasound (US). Each of these imaging modalities has its own advantages and disadvantages, and therefore, a multimodal approach combining two techniques is often adopted to generate complementary anatomical and functional information of the disease (Anderson and Lewis, 2017).
The key requirement for any molecular imaging procedure is a chemical agent, called the imaging probe. This probe typically consists of two chemical entities: one that produces a signal for imaging and another, a targeting vector, which enables the probe to specifically visualize, characterize and quantify biological processes in living systems. The optimization of the probes involves several different aspects ranging from the design of imaging units that exhibit enhanced sensitivity and lower toxicity, to the control of the structural and electronic features of the targeting moiety responsible for the molecular recognition (Long and Wong, 2015). In this research topic we present a series of original research and review articles that summarize the chemistry of molecular imaging, both in terms of optimization of the MI probe and in terms of application of different imaging techniques such as MRI, PET/SPECT, OI, and US.
The optimization of MRI contrast agents (CAs) is pursued to obtain more stable, safer and more efficient probes for potential application in molecular imaging. In particular, two dinuclear Gd(III) complexes and their relaxometric characterization have been reported by Leone et al. demonstrating that a significant contribution of second sphere water molecules is responsible for the strong relaxivity enhancement observed over a large range of magnetic field strengths. Regarding Mn(II) complexes of 12-membered macrocyclic ligands as a promising alternative to Gd-based CAs, Tircsó et al. have reviewed the relationship between ligand structure and physicochemical properties of the complexes. The rigidity of the macrocycle and proper selection of the donor atoms in the sidearm are the key structural features that control the thermodynamic and the dissociation kinetic properties of these macrocyclic Mn(II) complexes.
The synthesis, characterization and handling of Eu(II)-containing complexes have been reviewed by Basal and Allen showing how these air-sensitive probes can provide an intriguing and promising approach to new MRI molecular imaging procedures. The review especially focuses on the reduction of Eu(III) to produce Eu(II)-containing complexes and on the handling of Eu(II)-containing samples to prevent oxidation and obtain accurate data.
Chemical Exchange Saturation Transfer (CEST) continues to attract increasing attention as an alternative MR imaging modality to T 1 shortening agents. A contribution from Farashishiko et al. reports on an attempt to improve the sensitivity of these agents by incorporating a large payload of paraCEST agents into a reverse-assembled nanocapsule. Unfortunately, the result was not an amplification of the CEST effect, but quenching of the signal, attributed to an increase of the transverse relaxation rate of chelate protons caused by slow molecular tumbling of the complex in the nanosized system. 19 F-containing imaging probes can be advantageously employed in MRI and Magnetic Resonance Spectroscopy (MRS) because virtually there is no background 19 F MR signal in vivo. In the present topic, theories and strategies of improving the sensitivity of 19 F probes with paramagnetic metal ions have been reviewed by Peterson et al. In particular, the paper focuses on a theory that predicts the impact of certain molecular parameters on the sensitivity of fluorine-based probes.
The in vivo application of MRI-theranostic probes whose activation is induced by ultrasound, thermal or mechanical effects (sonosensitive probes) has been reviewed by Garello and Terreno. This work shows how these probes can be used for realtime monitoring of triggered drug release. These liposome based nano/microvesicles are composed of a biocompatible membrane responsive to US and an aqueous core loaded with a MRI probe and a therapeutic agent. A significantly better therapeutic effect was observed using US triggered drug release in comparison to traditional therapies.
The investigation of the luminescence properties of a Tb(III)-DOTA-calix[4]arene derivative was carried out by Mayer et al. with the aim to design dual MR/optical imaging probes. The paper shows how the calix[4]arene core with its four aromatic rings acts as an effective sensitizer of Tb-centred luminescence but different substituents on the lower rim can cause micellar aggregation leading to a significant decrease in the intensity of Tb(III) luminescence.
A dual-modality iron oxide nanoplatform for in vivo targeted SPECT and MRI investigation of tumor vascularization has been developed by Tsoukalas et al. The NPs were coated with 99m Tc radiolabeled Bevacizumab (BCZM) monoclonal antibodies (specific affinity to vascular endothelial growth factor-VEGF-A-receptor). Initial in vivo SPECT and MRI studies revealed the suitability of Fe 3 O 4 -DMSA-SMCC-BCZM for targeted dualmodality imaging.
The use of conjugates comprised of more than one targeting biomolecule (multimers) is a well-established and straightforward way to enhance the target affinity and uptake of radiotherapeutics. For this purpose, Wurzer et al. designed a DOTA-tetraphosphinate chelator (DOTPI) possessing four terminal carboxylic acid moieties to obtain tetrameric bioconjugates. The favorable properties of the 177 Lu labeled tetrameric DOTPI(PSMA) 4 conjugates for targeted radionuclide therapy have been demonstrated in in vitro and in vivo studies.
In order to rationalize the influence of metal ion contamination [e.g., Ti(IV), Fe(III), Cu(II), Zn(II) or Al(III)] on 68 Ga labeling, the physicochemical properties of Ga(TRAP) and Fe(TRAP) (TRAP = triazacyclononane phosphinic acid) were investigated in detail by Vágner et al. Equilibrium and kinetic data showed that the stability constants and the dissociation rates of Ga(III)-and Fe(III)-complexes are very similar. However, the slower formation of Fe(TRAP) allows selective labeling of TRAP with 68 Ga(III) even in presence of Fe(III) contamination in the eluate.