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PubMed2005

Non-invasive molecular imaging of beta-adrenoceptors in vivo: perspectives for PET-radioligands.

Recently, the spectrum of molecular imaging devices such as positron emission tomography (PET) was further expanded by the now clinically available combined imaging modalities such as PET-CT and the preclinically used small animal PET scanners. These are powerful tools that can bridge the gap between preclinical and clinical evaluation studies of new radiotracers for molecular imaging of healthy and diseased states in vivo. The beta-adrenoceptor (beta-AR) radioligands discussed in this review represent a class of molecular probes for the non-invasive in vivo assessment of beta-AR density eg. in the heart with PET. The beta-AR radioligands (S)-[11C]CGP 12177 (1) or (S)-[11C]CGP 12388 (2) are currently investigated in clinical studies with PET. Additionally, subtype-selective beta1-AR radioligands are used in preclinical research which show potential for the diagnostics of the "beta1-AR organ" as such the heart can be defined. Non-invasive quantification of beta-ARs could facilitate the accurate choice and control of therapeutic interventions. Here we summarize the state-of-the-art of the radiochemistry of radioactive beta-AR radioligands.

Adrenergic beta-Agonists↗

PubMed2000

Radiopharmaceuticals for the visualization of infectious and inflammatory lesions.

Many radiopharmaceuticals have been introduced for the scintigraphic demonstration of infectious and inflammatory lesions and some of them are currently in clinical use. They can be classified into two major categories according to their specificity. Specific radiopharmaceuticals include in vitro labeled leukocytes, radio-labelled monoclonal antibodies, and receptor specific small proteins and peptides. Nonspecific radiopharmaceuticals include radiolabelled nanocolloids, liposomes, macromolecules such as human immunoglobulin, dextran and human serum albumin, various small molecules and ions. In this review article radiopharmaceuticals in their respective groups are discussed as to the efficacy, and other parameters such as the physical characteristics of the radionuclides used, radiochemistry involved, availability, cost and biodistribution, emphasizing recent developments.

Animals↗

PubMed2004

The use of radiolabeled compounds for ADME studies in discovery and exploratory development.

Radiolabeled compounds are excellent investigative tools and widely used to carry out ADME studies during drug discovery and development stages. The most commonly used radioisotopes are 14C and 3H. 3H materials are generally easier to synthesize than 14C materials. Therefore, a variety of probes and substrates used in in vitro assays are labeled with 3H. Since synthesis of 14C material requires intensive resources, it is usually not available until after a molecule is considered for potential development or after the molecule enters the development phase. Improvement in the technology in radiochemistry has enabled the use of radiolabeled compounds earlier in pre-clinical and clinical development to address mechanistic issues. For in vitro studies, radiolabeled probes are utilized to test affinity with various transporters, to perform metabolism comparison among species and to assess possible formation of reactive metabolites. For in vivo studies, radiolabeled compounds are employed to identify and elucidate metabolites formed, to investigate the extent of absorption, bioavailability, tissue distribution, mass balance, routes of excretion, and pre-systemic metabolism. Due to the significant impact of radiolabeled studies on drug development, these studies will be performed earlier than have been in the past and will continue to be an integral part of drug discovery and development.

Animals↗

PubMed2004

Radiolabeled compounds in diagnosis of infectious and inflammatory disease.

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.

Humans↗

PubMed2004

PET imaging of opioid receptors in pain: progress and new directions.

The endogenous opioid system plays a central role in pain. Recent advances have permitted imaging of opioid receptors by PET in human subjects while experiencing pain and detection of changes in receptor occupancy. The ability to perform these types of studies is dependent on the development of opioid tracer ligands labeled with positron emitting isotopes. This article follows the development and radiochemistry of opioid tracer molecules through their use in human subjects and subsequent application to the study of pain. The role of mu, delta and kappa opioid receptors in pain is reviewed. Occupancy changes in mu receptors have been observed with PET in human subjects subjected to experimental pain paradigms. The implication of this approach to the study of pain and pain syndromes, and possible clinical applications, is also addressed.

Aging↗

PubMed1999

Oncogenes, cancer and imaging.

At the dawn of the 21st century, nuclear oncology is undergoing a formidable and rapid mutagenesis. The progress in radiochemistry, radiopharmacy and, foremost, the advances in molecular oncology are the determinant mutagenic factors. Mutation, amplification, deletion or translocation of deoxyribonucleic acid segments in proto-oncogenes and tumor suppressor genes also called anti-oncogenes account for the uncontrolled cell growth and proliferation resulting in cancer. The astonishing developments in peptide and nucleic acid chemistry have opened the door for the development of new, highly specific probes such as antisense, aptamer and peptidomimetic molecules to image the oncogenes and anti-oncogenes transcriptional (messenger ribonucleic acid) and translational (protein) products involved in carcinogenesis. In this article, I shall review the basic molecular mechanisms of carcinogenesis and describe the molecular probes that are currently being developed.

Animals↗

PubMed1991

Whither, or wither nuclear medicine?

In summary it appears that the future of the use of radionuclide procedures will show a continual increase in demand, utilization and growth of Nuclear Medicine as a discipline. The future of nuclear medicine physicians is less clear. Can they continue as a Renaissance model, interpreting all studies on all organs with equal expertise, or will they gradually be absorbed into organ or organ imaging sections to become a specialist on all imaging techniques on that organ? Is it true that the high technological advances that have been incorporated into Nuclear Medicine may be difficult to integrate into another discipline. For example, PET imaging is very much a part of Nuclear Medicine now and its expected growth in the future, along with the accompanying cyclotron and radiochemistry complexities, may prove to be a very large bite for any other discipline to follow. This integration, if it occurs, will not be overnight. Few radiologists practicing today in non-nuclear medicine areas would feel comfortable assuming the responsibilities of radionuclide studies, based on their three to six month stint in Nuclear Medicine.(ABSTRACT TRUNCATED AT 250 WORDS)

Data Collection↗

PubMed1999

Positron emission tomography: radioisotope and radiopharmaceutical production.

A Centre for Positron Emission Tomography (PET) has been operational within the Department of Nuclear Medicine at the Austin & Repatriation Medical Centre (A&RMC) in Melbourne for seven years. PET is a non-invasive imaging technique based on the use of biologically relevant compounds labelled with short-lived positron-emitting radionuclides such as carbon-11, nitrogen-13, oxygen-15 and fluorine-18. The basic facility consists of a medical cyclotron (10 MeV proton & 5 MeV deuteron), six lead-shielded hotcells with associated radiochemistry facilities, radiopharmacy and a whole body PET scanner. A strong radiolabelling development program, including the production of 15O-oxygen, 15O-carbon monoxide, 15O-carbon dioxide, 15O-water, 13N-ammonia, 18F-FDG, 18F-FMISO, 11C-SCH23390 and 11C-flumazenil has been pursued to support an ambitious clinical and research program in neurology, oncology, cardiology and psychiatry.

Drug Design↗

PubMed2001

[Application of radioactive substances in nuclear medicine research: current trends and radiation exposure of study subjects].

AIM: Analysis of the application of radioactive substances in research in the field of nuclear medicine in human beings and of the resulting radiation exposure to study subjects. METHODS: Assessment of applications for approval submitted in accordance with Paragraph 41 of the Radiation Protection Ordinance, evaluated by the Federal Office for Radiation Protection together with the Federal Institute for Pharmaceuticals and Medical Products, within the period from 1997 to 1999. RESULTS: The focus of the studies on the diagnostic application of radioactive substances in medicine evaluated has, since 1998, shifted from oncological to neurological and psychological aspects, while, at the same time, the number of PET studies increased constantly. The proportion of healthy study subjects included in the diagnostic studies increased from 7 to 22%. The number of therapeutic applications of radioactive substances has, since 1997, undergone a three-fold increase, and in the process of this, the focus of attention lay within the area of radioimmuno-therapy and endovascular brachytherapy. The effective dose was, among up to 49% of the investigated healthy study subjects higher than 5 mSv, and among up to 6% of these subjects was at levels of over 20 mSv. Up to 22% of the patients received, within the scope of diagnostic studies, an effective dose of between 20 and 50 mSv. An exceeding of the 50 mSv limit occurred among up to 3% of the patients. CONCLUSIONS: In spite of the increasing numbers of PET applications, conventional nuclear medicine has maintained its importance in the field of medical research. Further developments in the areas of radiochemistry and molecular biology led to an increase in the importance of radio-immuno therapy. The evaluation of new radiopharmaceuticals and the extension of basic biomedical research, resulted in an increase in the proportion of healthy study subjects included in the studies. The radiation exposure among subjects resulting directly from the studies showed, for the period of evaluation, an overall trend towards reduction.

Humans↗

PubMed1999

Dr. Nobuo Yamada's whole life, dead due to his radioactive studies at the Radium Institute (Part 2): in celebration of the 100-year anniversary of the discovering radium, 1898-1998.

On the occasion of the 100th anniversary of the discovery of radium by M. & Mme. Curie, commemorative lecture meetings were held in Japan in 1998 as follows. 1) The 42nd Symposium on Radiochemistry was held in Sendai on September 18. Dr. M. Sakanoue, Professor Emeritus Kanazawa University, presented a commemorative lecture entitled "Collaborative Research done by Irene Curie and Nobuo Yamada." He explained an outline of the studies on the measurement of long-range particles emitted by various radioactive substances such as polonium, radium and thorium. In addition to his lecture, I made a comment on the curriculum vitae of Dr. N. Yamada. 2) On October 24, another commemorative lecture meeting was held in Tokyo. At this meeting, Helene Langevin-Joliot, daughter of Irene Joliot-Curie presented a lecture on whole life of M. & Mme. Curie as a guest speaker. After meeting ended, I had the opportunity to talk with her personally. I have been investigating references describing the cause of death of Dr. Nobuo Yamada and found the following. The inadequacy of an apparatus for protection from radioactivity in the 1920s and reference to the death of Dr. Nobuo Yamada specifically were described in an article written by Dr. S. Iimori and in a nonograph written by Dr. M. Furukawa. The tragedy of scientists who suffered severe radiation syndrome during experiments at the Radium Institute was described in a biography of Marie Curie written by Susan Quinn.

Academies and Institutes↗

PubMed1998

[Radioimmunoimaging of bladder tumor with the intravesical administration of technetium -99m labelled monoclonal antibody].

OBJECTIVE: To make radioimmunoimaging of bladder tumor simple, safe and reliable. METHODS: Anti-human bladder carcinoma cell line BIU-87 monoclonal antibody-BDI-1 was labelled with technetium -99m by direct mercaptoethanol reducing method. RESULTS: The labelling rate was 69.6% and the radiochemistry pruity was higher than 95%. 33 patients received radioimmunoimaging of bladder tumor with the intravesical administration of technetium -99m labelled monoclonal antibody. The false positive rate was zero. 88.5% of all 29 bladder cancer patients had got positive immunoscintigraphy results, and 65.2% of them were confirmed by cystoscopic results. Both primary and recurrent tumor could be detected clearly and the smallest tumor detected was 0.5 cm in diameter. There were some differences between the radioimmunoimaging and cystoscopic results in 7 of 11 multitumor cases, which included tumor size, number and location. CONCLUSION: It is required to use more suitable isotopes and/or monoclonal antibodies to increase its sensitivity.

Administration, Intravesical↗

PubMedDate not supplied

[Neuropharmacology and receptor studies in the elderly].

Functional brain imaging has provided unique and exciting opportunities to strengthen our knowledge of the biological substrate of the aging brain and neuropsychiatric disorders. Positron emission tomography (PET) is a particularly powerful tool for quantifying the neurobiological correlates of cognition, mood and behavior. Initial PET studies of aging, psychiatric disorders and neurodegenerative disease focused primarily on generalized physiological parameters such as cerebral blood flow and metabolism, and early neuroreceptor imaging studies relied on relatively non selective markers. New, selective receptor radioligands now offer a previously inaccessible means to investigate the dynamic relationships among neurochemistry, aging and psychopathology in vivo. This approach has substantial advantages over peripheral (platelet and cerebrospinal fluid) markers, neuroendocrine challenge studies, animal models, and postmortem receptor binding assays. Advances in tracer kinetic modeling, magnetic resonance imaging (MRI) to PET registration, radiochemistry techniques, instrumentation and image processing have helped pave the way for increased emphasis on functional imaging studies of neuropsychiatric disorders of the elderly. The capability to correct PET image data for the confounding effect of cerebral atrophy permits relationships among age related brain changes and neurobiological disease mechanisms to be more accurately examined in the course of normal aging and in elderly patient populations.

Aging↗

PubMed2002

"High specific activity" radiotracers for metallo-toxicological studies: cyclotron and nuclear reactor production, radiochemical separation and "quality control": platinum, iridium, gold, copper and gallium.

Very High Specific Activity RadioNuclides, HSARN, are a powerful tool to label a wide variety of chemical elements and compounds present in the biosphere in ultra-trace amounts. Medium and high Z radionuclides, can be produced by irradiation in light-ions accelerator and sometimes nuclear reactor. If the nuclear reaction product has atomic number different from irradiated target, it is possible separating the radioactive nuclide from irradiated target, without addition of isotopic carrier. These kinds of radionuclides are named No Carrier Added, NCA, and their specific activity is very high and can reach values close to the theoretical Carrier Free one. The true specific activity must be determined by use of very sensitive radioanalytical techniques. If a low isotopic dilution factor is obtained, these radiotracers are used to label inorganic species and complexes of elements, which are presently introduced into the echo-systems by human activities. New production methods for NCA Pt, Ir, Au, Cu and Ga radiotracers are presented, with some details on radiochemistry and quality controls.

Copper↗

PubMed1992

Principles and clinical applications of positron emission tomography.

The basics of positron emission tomography (PET) are presented, including the physics, instrumentation, and radiopharmaceuticals involved; the clinical and research applications; and the cost. In PET, organic molecules labeled with positron-emitting radionuclides are injected or inhaled, and the high-energy photons produced by annihilation events are detected by paired, integrated crystal detectors. A computer uses the lines of origin of these photons to reconstruct a three-dimensional map of a functioning organ system. The positron-emitting radionuclides most often used are carbon 11, oxygen 15, nitrogen 13, fluorine 18, and rubidium 82. PET imaging centers usually consist of a cyclotron facility, a radiochemistry facility, a PET scanner, and computers for image reconstruction. Radiopharmaceuticals used in PET may be divided into blood flow-imaging agents, metabolic imaging agents, and drug receptor-imaging agents. Although PET is still primarily a research tool, it has shown diagnostic potential in neurology, cardiology, and oncology. It has also shown promise as a tool for pharmacologic assessment, as in studies of the effects of the fluorinated quinolones on cerebral blood flow and glucose metabolism. PET may become important in drug development because it yields specific information relatively noninvasively. A single study carries an average break-even price tag of $1500-$2000; rigorous cost-benefit analyses should be conducted before society is asked to subsidize such costs. Positron emission tomography is a frontier technology for which valuable clinical applications are being discovered. Pharmacists can contribute enormously to PET applications and at the same time establish a unique subspecialty for the profession.

Humans↗

PubMed2005

Perspectives on cancer therapy with radiolabeled monoclonal antibodies.

With the approval of 2 radiolabeled antibody products for the treatment of non-Hodgkin's lymphoma (NHL), radioimmunotherapy (RIT) has finally come of age as a new therapeutic modality, exemplifying the collaboration of multiple disciplines, including immunology, radiochemistry, radiation medicine, medical oncology, and nuclear medicine. Despite the many challenges that this new therapy discipline has encountered, there is growing evidence that RIT can have a significant impact on the treatment of cancer. Although follicular NHL is currently the only indication in which RIT has been proven to be effective, clinical trials are showing usefulness in other forms of NHL as well as in other hematologic neoplasms. However, the treatment of solid tumors remains a formidable challenge, because the doses shown to be effective in hematologic tumors are insufficient in the more common epithelial cancers. Nevertheless, there has been progress in locoregional applications and in the treatment of minimal residual disease. There is also optimism that pretargeting procedures, including new molecular constructs and targets, will improve the delivery of radioactivity to tumors, do so with less hematologic toxicity, and become the next generation of RIT.

Animals↗

PubMed2005

Current status of therapy of solid tumors.

The recent approval of 2 radiolabeled antibodies against cluster designation 20-positive lymphoma has led to a resurgence of interest in radioimmunotherapy. As was the case with chemotherapy development, progress has been most marked in the hematologic neoplasms, both in myeloablative and in nonmyeloablative therapeutic strategies. Success in the radioimmunotherapy of solid tumors has lagged because of the immunogenicity of murine proteins and the relatively slow clearance of humanized intact immunoglobulins. Genetic engineering has enabled the development of a variety of antigen-binding constructs of various sizes and immunobiologic characteristics. Developments in radiochemistry as well as production of an increasing number of radionuclides with therapeutic potential or optimal imaging characteristics have spurred tailored therapeutic strategies that include dosimetry and considerations of tumor burden. Such progress has generated pivotal studies that will establish the radiobiologic paradigms for successful radioimmunotherapy of solid tumors. This review will describe seminal studies that have paved the way to an understanding of radioimmunotherapy in solid tumors. Finally, the authors' views of the future of this promising cancer therapy will be presented.

Animals↗

PubMed1992

Positron emission tomography studies in parkinsonism.

PET imaging is a rapidly expanding technique with growing clinical utility. In this review, we have discussed the contribution of functional neuroimaging with PET in elucidating the pathophysiology of parkinsonism. In addition, we emphasize the growing role of this technique in the clinical setting. FDG/PET has become increasingly available at major medical centers and is especially suitable as an aid in the clinical assessment of patients with akinetic-rigid or other movement disorders. Although this technique is essentially quantitative and ideally suited for broad population studies, qualitative and semiquantitative approaches may suffice in the evaluation of individual patients. To the extent that several of the functional imaging models are linear with raw count rates, blood sampling may not be needed in each instance. Moreover recent advances in SPECT perfusion imaging may permit the extension of PET diagnostic criteria to other imaging modalities that are less costly and more accessible in the community setting. New statistical methods for the detection of regional metabolic covariation patterns hold special promise for the development of disease-specific imaging markers, which may permit rapid differential diagnosis, improved drug trials, and possible preclinical detection. F-dopa/PET has provided many important in vivo insights into the nigrostriatal dopamine system and its role in the development of parkinsonism. In contrast to FDG/PET, this technique demands specialized radiochemistry, plasma analysis, and modeling approaches that currently restrict its applicability to a few research PET centers. Several promising developments in radiochemical synthesis, data acquisition, and kinetic modeling may simplify the technique sufficiently to be used in the clinical domain. F-dopa/PET holds particular promise in preclinical screening of individuals at risk for Parkinson's disease on genetic or environmental grounds. This has great significance in view of the concurrent availability of potentially neuroprotective pharmaceuticals. Similarly this technique has great potential in objectively measuring rates of disease progression in normal and treated populations. We believe that with greater availability, these PET techniques and others currently under development will have significant impact on the diagnosis and management of patients with Parkinson's disease and related disorders.

Brain↗

PubMed2006

Advances in cancer therapy with radiolabeled monoclonal antibodies.

UNLABELLED: Two radiolabeled antibody products for the treatment of non-Hodgkin's lymphoma have been approved, thus indicating that cancer radioimmunotherapy (RAIT) has finally come of age as a new therapeutic modality, exemplifying the collaboration of multiple disciplines, including immunology, radiochemistry, radiation medicine, medical oncology, and nuclear medicine. Clinical trials are showing usefulness in other hematological neoplasms, but the treatment of solid tumors remains the major challenge, since the doses shown to be effective in hematological tumors are insufficient in the more common epithelial cancers. Nevertheless, use of RAIT in locoregional applications and in the treatment of minimal residual disease have shown promising RESULTS: There is also optimism that pretargeting procedures, including new molecular constructs and targets, will improve the delivery of radioactivity to tumors with less hematologic toxicity, and thus may become the next generation of RAIT.

Antibodies, Monoclonal↗