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.
19F-containing imaging probes can be advantageously employed in MRI and Magnetic Resonance
Spectroscopy (MRS) because virtually there is no background 19F MR signal in vivo.
In the present topic, theories and strategies of improving the sensitivity of 19F
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 real-time 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 99mTc 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 Fe3O4-DMSA-SMCC-BCZM for targeted dual-modality
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 177Lu 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 68Ga 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 68Ga(III)
even in presence of Fe(III) contamination in the eluate.
Author contributions
The authors have made a substantial, direct, and intellectual contribution to the
work, and approved it for publication.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.