The discovery and development of a biologically active molecule with therapeutic properties
is an increasingly complex task, highly unpredictable at the early stages and frequently
marked, in the end, by high rates of failure. As a consequence, the overall process
leading to the production of a successful drug is very long and costly. The improvement
of the net outcome in drug discovery and development would require, amongst other
important factors, a good understanding of the molecular events that characterize
the disease or pathology in order to better identify likely targets of interest, to
optimize the interaction of an active agent (a small molecule or a macromolecule of
natural or synthetic origin) with those targets, and to facilitate the study of the
pharmacokinetics, pharmacodynamics and toxicity of an active agent in both suitable
models and human subjects.
This series of articles has been brought together to highlight new developments and
applications of imaging techniques with the objective of performing pharmacological
studies in vivo, in animal models as well as in humans. Imaging has the ability to
study various biological and chemical processes non-invasively in living subjects
in a longitudinal manner. For this reason, imaging technologies have become an integral
part of the drug-discovery and development program and are commonly used in both preclinical
and clinical stages. The anatomical, functional, metabolic, and molecular information
that becomes accessible through imaging provides invaluable insights into disease
mechanisms and mechanisms of drug action.
Computerized tomography (CT) and magnetic resonance imaging (MRI) belong to the so
called anatomy-based imaging techniques. They exploit intrinsic tissue characteristics
as the source of image contrast. However, both modalities may also rely on the use
of agents to highlight some particular contrast. The development of MRI contrast agents
has been briefly discussed by Terreno and Aime. The great advantage of CT and MRI
in the context of drug research is their translational nature. Thus, they may be used
for compound testing in animal models of diseases and further also in clinical studies.
Here, Ashton et al. reviewed non-contrast-enhanced and contrast-enhanced micro-CT
applications for the study of anatomy and function in small rodents. Recent advances
of cardiovascular, neurovascular and renal MRI in small rodents were addressed by
Niendorf et al.; Jonckers et al. described the way functional MRI (fMRI) can be used
to study the effects of pharmacological modulations on brain function in a non-invasive
and longitudinal manner. Finally, Marzola et al. highlighted the use of imaging, especially
micro-CT and MRI, for the in vivo identification, quantification, and functional characterization
of adipose tissues in animal models of obesity, mainly from the point of view of biophysics
As the domain of imaging sciences transitions from anatomical/functional to molecular
applications, the development of molecular probes becomes crucial for the advancement
of the field. Positron emission tomography (PET) and single photon emission computed
tomography (SPECT) are molecular imaging techniques of great interest within pharmacological
research. They have the ability to provide biomarkers that permit spatial assessment
of pathophysiological molecular changes and therefore objectively evaluate and follow
up therapeutic responses. They are known primarily for their clinical applications,
however, animal studies are also feasible, emphasizing the translational character
of these techniques. Here, Declercq et al. illustrated the use of SPECT and PET in
the context of drug development for Alzheimer's disease (AD), specifically discussing
a number of biomarkers that are supporting emerging clinical therapies for this disease.
Targeted therapy with monoclonal antibodies (mAbs) is an avenue pursued in the context
of personalized medicine, particularly for cancer patients. The assessment of in vivo
biodistribution and tumor targeting of mAbs to predict toxicity and efficacy is an
important step toward drug development for individualized treatments. Jauw et al.
discussed how PET employing zirconium-89 (89Zr)-labeled mAbs, an approach also termed
89Zr-immuno-PET, can be used to visualize and quantify the uptake of radiolabeled
mAbs in tumors. Overall, 89Zr-immuno-PET provides imaging biomarkers to assess target
expression as well as tumor targeting of mAbs.
Ultrasound is a classical diagnostic imaging technique often used to locate a source
of a disease or to exclude any pathology. It is largely used to visualize internal
body structures, such as tendons, muscles, joints or vessels, and internal organs.
Besides its ability to provide anatomical information, ultrasound can also display
information on blood flow, motion of tissue over time, and tissue stiffness. Compared
to other prominent methods of medical imaging, ultrasound has several advantages,
including the acquisition of images in real-time, it is portable and can be brought
to the bedside, it is substantially lower in cost and does not use harmful ionizing
radiation. Drawbacks of ultrasonography include limited field of view, difficulty
in imaging structures behind bone and air, and its dependence on skilled operators.
Seitz et al. showed that ultrasound is sufficiently reliable to measure acute and
chronic changes in the diameter of splanchnic veins in intact rats. Although ultrasound
imaging of the abdominal vessels is not novel in experimental research or in the clinics,
assessment of diameter changes in multiple splanchnic vessels is new as they relate
to venous capacitance.
Recently, ultrasound has also entered the arena of molecular imaging. Paefgen et al.
reviewed here the development of bubble-based contrast agents for ultrasound imaging
and for imaging drug delivery. The basis for molecular imaging applications is the
coupling to the shell of bubbles of specific ligands that bind to marker molecules
in the area of interest. Also, bubbles may be loaded with or attached to drugs, peptides
or genes. By applying ultrasound pulses, the bubbles are destroyed, leading to a local
release of the entrapped agent. The use of microbubble-assisted ultrasound to deliver
chemotherapeutic agents has been extensively discussed by Lammertink et al. One specific
class of agents that might be of interest for such delivery are S-tanathin functionalized
liposomes, as presented here by Fan et al. S-thanatin is a short antimicrobial peptide
with selective antibacterial activity (Wu et al., 2010).
Optical imaging adds to the realm of molecular imaging approaches. Main advantages
of optical imaging are safety and cost-effectiveness. Major drawbacks, however, are
the high scattering and high absorption of light in living tissues. Arranz and Ripoll
described the latest advances in optical in vivo imaging with pharmacological applications,
with special focus on the development of new optical imaging probes in order to overcome
the strong absorption introduced by different tissue components, especially hemoglobin,
and the development of multimodal imaging systems in order to overcome the resolution
limitations imposed by scattering. Despite being mostly limited to small rodents,
there is a large interest for optical imaging in the context of pharmacological research,
as optical imaging is useful for selecting and validating potential novel probes in
an economic and safe (radiation free). The in vivo performance of optical probes may
predict the outcome of the ensuing and much more involved SPECT/PET tracer development
(Sandanaraj et al., 2010).
Animal models have in general been considered of importance in the drug discovery
process. On the other hand, the widespread use and evolution of imaging would not
have been possible without animal studies. Animal models have allowed, for instance,
the technical development of different imaging tools and probes. Santos et al. have
critically discussed the value of animal models in the context of cardiovascular imaging.
The focus in this series has been dedicated to in vivo macroscopic imaging applications
within pharmacological research. Nonetheless, microscopic imaging has also an important
role to play in this domain. As an example, Xu highlighted the latest advances in
hepatotoxicity, cardiotoxicity, and genetic toxicity tests utilizing cellular imaging
as a screening strategy.
In the domain of drug discovery, the pharmacological and biomedical questions constitute
the center of attention. In this sense, it is fundamental to keep in mind the strengths
and limitations of each analytical or imaging technique. In this series, our aim was
to illustrate the fact that the judicious application of a given technique to search
for answers to manifold questions arising during a long and painstaking path will
continue to rely on imaging as a must-have tool in drug discovery and development.
All three authors helped organizing the research topic, inviting authors, reviewing
manuscripts and writing the editorial.
Conflict of interest statement
NB is employed by Novartis Pharma AG, Basel, Switzerland. The other 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.