Articles
Targeted α-Particle
Therapy: A Clinical Overview, 2008, Vol: 1(3) Pp. 251-253
M. Salvatori, L. Indovina and L.
Mansi
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Quantification of SPECT and PET for Drug Development, 2008, Vol: 1(1) Pp. 17-21
Youngho Seo
[Abstract] [Full
Text Article]
Applications of Positron Emission Tomography in Neuropsychiatric
Pharmaceutical Drug Development, 2008, Vol: 1(1) Pp. 12-16
Jeffrey M. Miller, Dileep Kumar, J. John Mann and Ramin
V. Parsey
[Abstract] [Full
Text Article]
Radiopharmaceuticals for Drug Development: United
States Regulatory Perspective, 2008, Vol: 1(1) Pp. 2-6
Henry F. VanBrocklin
[Abstract] [Full
Text Article]
Development of Infection and Inflammation Targeting
Compounds, 2008, Vol: 1(1) Pp. 42-48
Peter Laverman, Chantal P. Bleeker-Rovers, Frans H.M.
Corstens, Otto C. Boerman and Wim J.G. Oyen
[Abstract] [Full
Text Article]
Radiopharmaceuticals, Drug Development and Pharmaceutical
Regulations in Europe, 2008, Vol: 1(1) Pp. 7-11
Piero A. Salvadori
[Abstract] [Full
Text Article]
99mTc-Labeled
Nanobodies: A New Type of Targeted Probes for Imaging Antigen
Expression, 2008, Vol: 1(1) Pp. 37-41
Virna Cortez-Retamozo, Tony Lahoutte, Vicky Caveliers,
Lea Olive Tchouate Gainkam, Sophie Hernot, Ann Packeu, Filip
De Vos, Chris Vanhove, Serge Muyldermans, Patrick De Baetselier and Hilde Revets
[Abstract] [Full
Text Article]
Recent Advances in Radiation Therapy of Cancer Cells:
A Step towards an Experimental and Systems Biology Framework, 2008, Vol: 1(1) Pp. 22-29
Petar M. Mitrasinovic and Marija L. Mihajlovic
[Abstract] [Full
Text Article]
Synthesis and Evaluation of [11C]SB207145
as the First In Vivo Serotonin 5-HT4 Receptor Radioligand for PET Imaging in Man, 2008, Vol: 1(2) Pp. 110-114
A.D. Gee, L. Martarello, J. Passchier, M. Wishart, C.
Parker, J. Matthews, R. Comley, R. Hopper and R. Gunn
[Abstract] [Purchase
Article]
Editorial: The
Role of Radiopharmaceuticals in Drug Discovery, 2008,
Vol: 1(1) Pp. 1
Dr. Kalevi Kairemo and Dr. Kim Bergström
Abstracts
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Targeted α-Particle
Therapy: A Clinical Overview, 2008, Vol: 1(3)
M. Salvatori, L. Indovina and L.
Mansi
Among radionuclides usable for tumor therapy, α-particle
emitters are characterized by a very high linear energy transfer
(LET) resulting in a larger number of ionizations in a range
corresponding to a cell diameter. Therefore, they can determine
a stronger therapeutic effect compared to low LET β-particle
emitters, producing their ionizations in a range up to many
millimeters. In fact, because the distance between the two
strands of DNA is almost the same as the distance between
two ionizations of α-particles,
DNA double strand breaks are induced with a high probability
that finally cause cell death due to inefficient repair. Conversely,
no therapeutic effect can be determined outside of concentrating
sites. Therefore, the short range of α-emitters
makes them powerful tools mainly when a therapeutic effect
has to be reached in a restricted area, as in the elimination
of minimal residual disease or in micro-metastases. Therapeutic
efficacy of α-emitter
radionuclides has been proven in numerous pre-clinical studies,
but up to today only three main human studies are reported,
including the treatment of myeloid leukemia by an anti-CD33
monoclonal antibody labelled by bismuth-213 (213Bi),
the therapy of patients with bone metastases from hormone-refractory
prostate cancer by radium-223 (223Ra)
and the loco-regional targeted radiotherapy with astatine-211(211At)-labelled
anti-tenascin monoclonal antibody in patients with recurrent
malignant brain tumours. The authors reviewed these human
reported studies, evaluating perspectives, advantages and
limitations of the targeted α-particle
therapy.
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Quantification of SPECT and PET for Drug Development, 2008, Vol: 1(1)
Youngho Seo
Development of a new drug faces multi-faceted sequences in
the pipeline. Once a drug candidate is identified, evaluation
process can be accelerated by in vivo noninvasive
imaging because there is a potential to use a smaller number
of animals and human subjects. Radionuclide imaging techniques,
such as single photon emission computed tomography (SPECT)
and positron emission tomography (PET) are directly translatable
imaging modalities that can be used in both animal models
of disease and humans. In addition, SPECT and PET provide
a highly sensitive means to track radiolabeled drugs, for
which the imaging process less likely perturbs biological
functions of animals and humans. Quantification of SPECT and
PET data when used for drug development is elusive. Often
times, in vivo SPECT and PET images of any drug candidate
are used as ‘flash’ show-and-tell scenarios while
actual data are obtained from ex vivo analyses. However,
once the need and the degree of quantification are defined
carefully, quantification of SPECT and PET can play an important
role in drug development and evaluation processes.
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Applications of Positron Emission Tomography in Neuropsychiatric
Pharmaceutical Drug Development, 2008, Vol: 1(1)
Jeffrey M. Miller, Dileep Kumar, J. John Mann and Ramin
V. Parsey
Positron Emission Tomography (PET) can be used to quantify
proteins of interest in the brain, assess the function of
these proteins, and quantify cerebral glucose metabolism and
blood flow. Its value in neuropsychiatric pharmaceutical drug
development is extensive, from the identification of relevant
pathophysiology in disease states, to measurement of blood-brain
barrier penetration and regional cerebral occupancy of a pharmaceutical
agent, to predictions of treatment outcome from a specific
pharmacologic intervention in a specific patient. In this
paper, we briefly review some basics of brain imaging using
PET, and describe its applications to the field of neuropsychiatric
pharmaceutical development, including relevant examples from
the existing literature. We conclude with a discussion of
future developments that will make PET increasingly available
and useful for such purposes.
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Radiopharmaceuticals for Drug Development: United
States Regulatory Perspective, 2008, Vol: 1(1)
Henry F. VanBrocklin
Imaging with radiopharmaceuticals is playing an increasingly
important role in the development of new drugs. At nearly
every step of the process imaging may be used to assess the
status of the candidate drugs and assist in determining the
lead molecules for further evaluation. Incorporating imaging
studies into the paradigm may ameliorate the temporal and
economic cost of drug development. Since 1975 radiopharmaceuticals
have been regulated as drugs and all human studies must be
carried out under an investigational new drug (IND) or radioactive
drug research committee (RDRC) protocol. The FDA released
the exploratory IND guidance in 2006 to highlight the flexibility
in the IND process while trying to stimulate new drug entry
into the approval pipeline. The exploratory IND also provides
a lower threshold for radiopharmaceutical and candidate drug
first in human studies, using the microdosing concept, that
may not be conducted under an RDRC protocol. The RDRC mechanism
permits the basic research studies with limited dose and numbers
of subjects. The RDRC regulations are 30 years old and the
full IND process remains burdensome for radiopharmaceutical
development. Therefore, it is essential that the regulatory
framework permit the approval of radiopharmaceuticals for
use in humans that is commensurate with the safety and applications
of the probes.
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Development of Infection and Inflammation Targeting
Compounds, 2008, Vol: 1(1)
Peter Laverman, Chantal P. Bleeker-Rovers, Frans H.M.
Corstens, Otto C. Boerman and Wim J.G. Oyen
Nuclear medicine offers powerful noninvasive techniques for
visualization of infectious and inflammatory disorders using
whole body imaging enabling the determination of both localization
and number of inflammatory foci. A wide variety of approaches
depicting the different stages of the inflammatory response
have been developed. Non-specific radiolabeled compounds,
such as 67Ga-citrate and
radiolabeled polyclonal human immunoglobulin accumulate in
inflammatory foci due to enhanced vascular permeability. Specific
accumulation of radiolabeled compounds in inflammatory lesions
results from binding to activated endothelium (e.g. radiolabeled
anti-E-selectin), the enhanced influx of leukocytes (e.g.
radiolabeled autologous leukocytes, anti-granulocyte antibodies
or cytokines), the enhanced glucose-uptake by activated leukocytes
(18F-fluorodeoxyglucose)
or direct binding to micro-organisms (e.g. radiolabeled ciprofloxacin
or antimicrobial peptides). Scintigraphy using autologous
leukocytes, labeled with 111In
or 99mTc, is still considered
the ”gold standard” nuclear medicine technique
for the imaging of infection and inflammation, but the range
of radiolabeled compounds available for this indication is
still expanding. Recently, positron emission tomography with 18F-fluorodeoxyglucose has
been shown to delineate various infectious and inflammatory
disorders with high sensitivity. New developments in peptide
chemistry and in radiochemistry will result in specific agents
with high specific activity. A gradual shift from non-specific,
cumbersome or even hazardous approaches to more sophisticated,
specific approaches is ongoing. In this review, the different
approaches to scintigraphic imaging of infection and inflammation,
already in use or under investigation, are discussed.
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Radiopharmaceuticals, Drug Development and Pharmaceutical
Regulations in Europe, 2008, Vol: 1(1)
Piero A. Salvadori
Radiopharmaceuticals have a long tradition of clinical and
research applications. Current legislation of developed Countries
includes these compounds in the regulatory environment of
medicinal products. Products used under a marketing authorisation
license and investigational radiopharmaceuticals are then
part of the clinical practice and scientific programs. Positron
Emission Tomography has induced a strong increase in the number
of potentially available radiopharmaceuticals and, beside
being a breakthrough in diagnostic nuclear medicine, has demostrated
its value as research tool. Drug Development Research is searching
new tools for reducing attrition and increasing efficiency
in the identification and development of new medicines. Molecular
Imaging, PET in particular seems to have important answers
to this demand. The regulatory environment in Europe is hence
revised in the perspective of utilisation of nuclear molecular
imaging as a supporting tool for DDR. Relevant documents from
European regulatory Agency (EMEA) as well as their essential
impact on radiopharmaceuticals have been summarised and discussed.
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99mTc-Labeled
Nanobodies: A New Type of Targeted Probes for Imaging Antigen
Expression, 2008, Vol: 1(1)
Virna Cortez-Retamozo, Tony Lahoutte, Vicky Caveliers,
Lea Olive Tchouate Gainkam, Sophie Hernot, Ann Packeu, Filip
De Vos, Chris Vanhove, Serge Muyldermans, Patrick De Baetselier and Hilde Revets
Introduction: The development of specific
radiolabeled probes towards molecular markers in vivo has gained interest as targeted imaging allows for a more
accurate detection of diseases. We investigate the feasibility
of targeted imaging of cancer antigens using the variable
domain of single chain camelid antibodies (Nanobodies®)
labeled with 99mTechnetium.
Nanobodies against carcinoembryonic antigen (CEA) were used
as a model.
Methods: His6-CEA1
Nanobodies were generated and labeled with 99mTc
at their His-tag using Tc(I)-tricarbonyl (Isolink, Mallinckrodt,
B.V., Petten, The Netherlands). The normal biodistribution
was assessed in healthy athymic mice by ex vivo analysis
at 1 and 3 h. In vivo targeting was evaluated in
the same mouse model bearing the CEA-positive LS174T tumour
or a CEA-negative A431 (human skin carcinoma) control tumour.
Pinhole SPECT imaging was performed at 3 hours after intravenous
injection of 90 MBq 99mTc-His6-CEA1
using a dual-headed gamma camera equipped with pinhole collimators.
Results: Radiolabeling efficiency was >
95%. General biodistribution showed intense renal uptake and
marked liver accumulation. Using pinhole-SPECT, the average
uptake of 99mTc- His6-CEA1
in LS174T (CEA positive) was significantly higher compared
to the A431 (CEA negative) control tumour: respectively 3.2
± 0.6 %IA/cm3 and
1.1 ± 0.2 %IA/cm3 (p< 0.05).
Conclusion: This study presents effective
labeling of Nanobodies with 99mTc
using Tc(I)-carbonyl chemistry and shows their potential as
a new type of specific probes for imaging antigen expression.
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Recent Advances in Radiation Therapy of Cancer Cells:
A Step towards an Experimental and Systems Biology Framework, 2008, Vol: 1(1)
Petar M. Mitrasinovic and Marija L. Mihajlovic
Due to rapid emergence of recombinant and antibody-based reagents
targeting specifically biomarkers of disease, radiolabeling
of antibodies has enabled the imaging and therapy of various
reactive oxygen species (ROS)-mediated pathological conditions,
such as cancer. Key contributions to this topic have been
dissected through two main standpoints: (1) immunotherapeutics
for advanced cancer care, including radiolabeling for cancer
imaging and therapy, design and testing of antibodies, and
radioimmunotherapy innovations for treating malignancies and
(2) search for a more efficient drug-targeted delivery method
for cancer therapy. Because tremendous progress has been made
in recent years, the future of cancer radioimmunotherapy is
suggested to be bright. The question, whether measurement
of oxidative damage to DNA has clinical relevance, is addressed.
To make biomarkers of oxidatively damaged DNA useful clinical
tools, further validation of biomarkers, followed by further
elucidation of the role of damage in disease, is suggested.
To understand the role of oxidative damage by focusing on
cellular processes under oxidative stress conditions, the
complementarities of mechanistic cell biology studies and
systems biology strategies in identifying new therapeutic
targets are demonstrated for liver cancer cells. Since most
morphological, physiological and molecular studies on death
of cells in tissues have been carried out on isolated cell
populations, systems biology is suggested to be a means of
overcoming known difficulties manifested by interference and
interaction with surrounding cells. The elucidation of fundamental
background of the ability of cells to interpret the same signal
action in distinct fashions - survival vs. death signal transduction
is suggested to facilitate more localized and efficient treatments
of various ROS-mediated pathologies.
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Synthesis and Evaluation of [11C]SB207145
as the First In Vivo Serotonin 5-HT4 Receptor Radioligand for PET Imaging in Man, 2008, Vol: 1(2)
A.D. Gee, L. Martarello, J. Passchier, M. Wishart, C.
Parker, J. Matthews, R. Comley, R. Hopper and R. Gunn
The aim of this work was to develop a PET radiotracer
which would enable the study of central serotonin 5-H4 receptors in man using positron emission tomography (PET).
A procedure was developed for labelling SB207145, a potent
and selective 5-H4 antagonist,
with the short-lived positron emitting radionuclide 11C.
Alkylation of the corresponding desmethyl compound with 11C-methyl
iodide afforded [11C]SB207145
in 50 – 60 % radiochemical yield (decay corrected to
end of cyclotron bombardment), specific activities of >
50 GBq/μmole
and radiochemical purities greater than 95%. PET studies in
pig showed [11C]SB207145
rapidly entered the brain reaching peak concentrations at
10 - 20 mins post administration, followed by washout from
tissue. In humans the tissue kinetics of the tracer was slower,
reaching peak tissue concentrations at 30 – 60 mins
post administration. In both species, the observed rank order
of regional brain concentrations was striatum > thalamus
> cortical regions > cerebellum, consistent with the
known distribution and concentration of 5-H4 receptors from in vitro studies. In pig, on administration
of 0.5 mg/kg SB207040, a selective 5-H4 antagonist, the specific binding of [11C]SB207145
was reduced to level of the cortex, demonstrating saturability
of the 5-H4 receptor population.
In conclusion, a new PET radioligand is described which enables
the study of 5-H4 receptors in vivo in humans for the first time using PET.
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Editorial: The Role of Radiopharmaceuticals in Drug
Discovery, 2008, Vol: 1(1)
In this first thematic issue of Current Radiopharmaceuticals,
the contributors have covered in great detail articles relating
to the drug development process within the emphasis of the
journal scope.
Radionuclide imaging together with other non-invasive imaging
techniques have found a prominent place in the whole drug
discovery and development process. The application of imaging
has the potential to alter the direction of the development
process. The fundamental questions to address are when in
the development timeline do you use these imaging techniques
and what is the current utilization of these imaging technologies?
Novel ‘imaging’ targets may have uncertain relationship
to specific disease states. Acceptable target is of little
value if its action cannot be modulated by therapeutics. Imaging
is a perfect method to assess these target biology questions.
Functional imaging endpoints can be used to evaluate target
effects in normal and diseased models, in different species,
and in the initial clinical studies. The longitudinal results
from functional imaging can be extremely valuable in the evaluation
of data from early clinical trials. The translational potential
of functional imaging techniques is most evident. The uncertainty
in potential drug candidates for example the efficacy and
toxicity can be quickly addressed to determine the course
of action. A preclinical imaging study may produce quantitative
results which can answer these types of translational questions.
Interest in functional imaging techniques has been motivated
especially by Food and Drug Administration (FDA) exploratory
Investigational New Drug (xIND) guidelines. Big Pharma has
made substantial investments in imaging centers throughout
the world to assist in the drug development process. Especially
in the area of oncology research by applying radionuclide
imaging techniques to determine the optimal protocol in early
clinical trials. It seems evident that non-invasive imaging
and especially radionuclide techniques will see increasing
use in the drug discovery and development process. In-house
imaging resources are increasing together with Contract Research
Organisation (CRO) services.
The ideas for these articles in this issue originated from
two symposia held in December 2006: one in Geneva organized
by GE Healthcare and another in Copenhagen, organized by Encorium
and Imanext. These Symposia were dedicated to Imaging in the
Drug Development Process. Similarly, The World Pharmaceutical
Congress held in June 2007 in Philadelphia had a dedicated
two-day symposium for ‘first-in-human’ phase 0
trial and microdosing studies. All these activities demonstrate
that imaging will be a keynote figure in constructing new
pharmaceuticals, already recognized by authorities. In this
issue regulatory aspects have been reviewed both from the
EU (Salvadori) and US perspectives (VanBroncklin).
It is hard to imagine future neuropsychiatric pharmaceuticals
without any imaging data and is reviewed explicitly by (Parsey et al.). The receptor occupancy studies and brain
receptor quantification are an essential part in lead candidate
selection (Seo et al.).
Cancer drugs are often chosen for further development according
to their tumor targeting abilities. Imaging techniques usually
characterize tumor tissue in a different manner; however,
radionuclide methods are most effective in the studies of
pharmacodynamics and pharmacokinetic models. In this issue
the role of systems biology has been reviewed in the development
of cancer drugs (Mitrasinovic and Mihajlovic). Drug delivery
systems couple the other imaging modalities (e.g.
magnetic resonance imaging (MRI), ultrasound (US) and optical)
to functional imaging modalities may find application in tumor
targeting compounds (Kairemo et al.). Bioengineered
chamelid antibodies (nanobodies) are a good example of using
radionuclide methods in targeted nanoparticle systems, and
possibly in cancer drug applications (Cortez-Retamozo et
al.).
Anti-inflammatory and antibiotic drugs are a major group of
pharmaceuticals, where tissue targeting maybe of importance.
These compounds have been reviewed by (Laverman et al.)
in this issue.
New possibilities have been developed to facilitate the drug
development process, such as exploratory IND and microdosing.
The concept of microdosing was originally linked to accelerator
mass spectrometry (AMS), but criteria can be fulfilled with
positron emission tomography (PET) and single photon emission
computed tomography (SPECT) imaging studies. Hopefully, this
first issue of Current Radiopharmaceuticals will
help the pharmaceutical industry to interact with the functional
imaging community. Today, radiopharmaceuticals are a prerequisite
for this communication; we hope that Current Radiopharmaceuticals serves as a good forum.
Dr. Kalevi Kairemo
Department of Oncology
Helsinki University Central Hospital
Imanext Ltd, Helsinki
Finland
Dr. Kim Bergström
Laboratory of Radiochemistry
University of Helsinki
Imanext Ltd, Helsinki
Finland
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