Current Medical Imaging - Volume 4, Issue 1, 2008

With progress of molecular medicine in recent years, imaging techniques are undergoing a tremendous development and improvement. They play a major role in the development of novel therapies since they generate informations about target expression as well as function, pathway activities and cell migration in the intact organism. Therefore, imaging enables the comprehensive characterization of therapeutic intervention and can be used in preclinical studies, pharmacokinetic (microdosing) studies, dose-finding studies, and proof-of-concept studies. PET and SPECT permit mapping and measuring the rate of physiological, biochemical and molecular process with the use of radiolabeled compounds and appropriate tracer kinetic models. David J. Yang, PhD., Professor of Radiochemistry at the University of Texas MD Anderson Cancer Center and Professors Hiroshi Fukuda, MD, PhD, Masatoshi Itoh, M.D. and Keizo Ishii, PhD at the Tohoku University organized the symposium on Imaging Science and Technology in Drug Discovery and Development with the long history of working and interest on various radiopharmaceuticals and PET technology to exchange ideas how to improve and promote imaging technology, especially PET and SPECT, and also to extend the investigational studies to clinical applications. The symposium was held on September 17 and 18, 2007 at the Sendai Kokusai Hotel, Sendai, Japan, sponsored by the Sendai Medical Imaging Clinic. The papers in this issue have been selected from the presentations at the symposium. Molecular imaging can accelerate several procedures in drug development and contribute to cost-reduction and also fast approval of candidate drugs. Challenges and opportunities in molecular imaging are overviewed by Yang et al. Tashiro et al. reviews the molecular imaging program at the Tohoku University with 30-year long history of basic and clinical researches using various radiopharmaceuticals, particulary neuroreceptors. Effective biomarkers have been desired both for diagnostic purpose and for the evaluation of the drug effects, and these are discussed for the proof-of-concept by Suhara and Kodaka. There are unique operational and safety requirements of PET radiotracer synthesis by the FDA, and this is presented by Sims-Mourtada et al., High resolution animal PET system using semiconductor CdTe detector is introduced by Ishii et al., Mawlawi et al. discuss multiple factors affecting quantification in PET/CT imaging to insure accuracy and reliability of PET outcome measurements. Cancer patients often manifest psychological or behavioral problems, and Tashiro et al. present a neuroimaging using PET and MRI in cancer patients. Prograssive deposition of amyloid plaque in the brain is an initiating event in the pathogenesis of Alzheimer's disease, and the PET as well as SPECT imaging of amyloid pathology in the living brain is discussed by Okamura et al. Khondkar et al. deal with the assessment of local brain metabolic responses during exercise in human with changing loads by regional changes of glucose metabolism. Overview of PET and SPECT utilization in clinical oncology is presented by Kim et al.

It is important to assess the deleterious effects of newly developed radiopharmaceutical in humans. These effects arise from the absorption of energy in tissues and depend on a number of factors such as organ size or location. Because of the variations of the factors from one individual to another, the effects of the radiopharmaceutical were evaluated on “reference” man. The radiation absorbed dose can be calculated semi-automatically by computer software “OLINDA”. From temporal sampling study or quantitative dynamic imaging study, area under the curve of percent injection dose in each organ can be calculated, and converted to the residence time of each organ. With the information of radionuclide, phantom model used as “reference” man, and the residence time of each organ, the OLINDA gives the absorbed dose of each organ and effective dose of the radiopharmaceutical.

Tohoku University has nearly a 30-year-long history of basic and clinical research in molecular imaging using radiopharmaceuticals. This article briefly overviews the various achievements of Tohoku University in the fields of oncology and neuroscience. It is noteworthy that most of the early data regarding oncology diagnosis using positron emission tomography (PET) were produced at the Cyclotron and Radioisotope Center of the university. Also, the center has various academic contributions to the filed of neuroscience. One of its major contributions is molecular imaging of histamine H1 receptors, and recent achievements in this topic are summarized in this paper. The histaminergic neuronal system is associated with various functions such as wakefulness, the sleep-wake cycle, appetite control, learning, memory and emotion. Using [11C]doxepin and PET, various studies have been conducted regarding physiological changes such as aging and pathological changes such as Alzheimer's disease, depression, and schizophrenia. In addition, histamine H1 receptor antagonists (antihistamines) are frequently used for the treatment of allergic disorders. These compounds can induce sedative side effects that can cause serious traffic accidents. Objective measurement of the sedative property of antihistamines was started in the early 1980s and was established at Tohoku University using H1 receptor occupancy as an index. In the future, PET will undoubtedly be used more frequently in drug development.

The purpose of this study was to clarify regional changes in brain metabolism induced by ergometer exercise at different loads. To reduce radiation exposure to subjects, we separated our volunteers into two groups: a resting control group and a task group. Three levels of exercise load were designed at 40% (light), 70% (moderate) and 80% (heavy) VO2max, corresponding to aerobic, intermediate and anaerobic metabolic conditions, respectively. The cerebral metabolic rate for glucose was calculated using [18F]fluorodeoxyglucose (FDG) and PET. Regional changes in glucose metabolism were evaluated using statistical parametric mapping (SPM2) with correction for global values. Covariate analysis between FDG uptake and task load identified a strong correlation in the primary motor cortex (precental gyrus) and cingulate cortex. Irrespective of the linearly increased region, strong activations in the motor leg areas were revealed by subtraction analyses during moderate and heavy exercise. Ergometer cycling activated areas in the prefrontal region at light load, and in the premotor, motor and parietal areas at higher loads. These regions are mainly involved in elaboration of movement and are part of the sensory association area for movement. However, activations in the areas responsible for motor control, such as the precentral gyrus were less evident.

Cancer patients often manifest psychological or behavioral problems and their brain functions may not always be normal. The purpose of this paper is to present an overview of the results of a series of studies regarding our examination of regional brain glucose metabolism of cancer patients. Following our preliminary study of Japanese cancer patients and a replication in German patients, we explored the possible underlying mechanism of hypometabolism using positron emission tomography with 18F-fluorodeoxyglucose (FDG PET). An increase in the score of Zung's Self-rating depression scale (SDS) was associated with decreased activity in the prefrontal cortex, anterior cingulate gyrus, and striatum. SDS scores and metabolic activity were negatively correlated especially in the basolateral prefrontal cortex. It seemed that the decreased activity in the prefrontal cortex was specifically associated with depressive mood. Further replications have demonstrated that FDG PET could be used for early detection and prediction of the future onset of psychiatric disorders among cancer patients. Recent advancement of magnetic resonance imaging (MRI) has enabled conductance of sophisticated volumetric analysis. Recent studies suggest that cancer patients with intrusive recollections (one of the key symptoms for diagnosing posttraumatic stress disorder) have significantly smaller amygdala and hippocampus. Thus, functional imaging techniques may be helpful in evaluating mild depression in cancer patients.

Effective biomarkers have been desired both for diagnostic purposes and for the evaluation of the effects of drugs. Positron emission tomography allows the visualization of several components of neurotransmissions, such as receptors and transporters. In vivo neuroimaging including neuroreceptor imaging and enzyme activity imaging has contributed to drug evaluation in terms of 1) rational drug dosing, 2) biodistribution of drug, 3) therapeutic rationale for drug use, and 4) mechanism of drug action [1]. In this article, we focused on the rational drug dosing of antipsychotic drugs and antidepressants using receptor occupancy and proof-of-concept of drugs, as well as new therapeutic methods for Alzheimer disease.

Positron Emission Tomography (PET) radiopharmaceuticals development has been experiencing explosive growth due to advances in functional imaging technology and exploration of molecular imaging targets for diagnosis and therapy. There are unique operational and safety requirements of PET radiotracer synthesis when compared to drug synthesis in general. In particular, strict sterility and pyrogenicity requirements, batch-to-batch reproducibility, yield, purity, specific activity, fast synthesis time (<2 or 3 T1/2), and radiation protection are defined. The FDA Center of Drug Evaluation and Research (CDER) mandate such requirements for human injection- a distinction between a radiochemical and a radiopharmaceutical. PC-controlled automation of synthetic process is essential for the widespread use of clinical PET providing an essential tool to complying with all aspects of necessary FDA requirements through current good manufacturing practice (cGMP) of human grade radiopharmaceuticals. The FDA regulates automated synthesizers as manufacturing equipment rather than as traditional medical devices.

In the past few years, PET and PET/CT imaging have increasingly been used as the modalities of choice for the diagnosis, staging and restaging of malignant disease. The main reason for the wide spread use of this modality primarily lies in its ability to accurately quantify the amount of activity concentration in tissues. However there are many factors that affect the accuracy of PET quantification. These factors can be grouped into three main categories. 1) Effects that are scanner dependent, 2) effects that are dependent on patient compliance with the study protocol, and 3) effects that are dependent on the PET study conditions. In addition, the growing use of PET/CT in the past few years as the improved mode of PET imaging due to its ability to combine functional information with anatomical localization, has also introduced a new category of factors that affect the accuracy of PET quantification. All of these factors should be accounted for whenever longitudinal or multi-center studies are performed in order to insure accuracy and reliability of PET outcome measures. The aim of this paper is to identify and describe each of the factors that impact PET quantification with special emphasis on methods that are currently used or are under development to overcome them.

Molecular imaging research has been focused on identification of tumor specific markers and the application of these markers for evaluation of patient response to radiation therapy, chemotherapy or chemo/radiotherapy. Though the opportunities are involved in molecule in licensing, yet, the challenges involves in regulatory compliance in investigative new drugs such as chemistry, manufacturing, control, pre-clinical pharmacology/toxicology and clinic protocol management. In this article, we reviewed the opportunities and challenges in molecular imaging using generator produced isotopes. 99mTc (technetium-99m), 68Ga (gallium-68) and 188Re (rhenium-188) are generator-produced isotopes which are readily-accessible and affordable. These generator produced isotopes were developed to label molecular targets for prediction of therapeutic response, monitoring tumor response to treatment and differential diagnosis. 188Re is a therapeutic radionuclide which can be used to target tumors and deliver lethal radiation due to high-energy β- emissions. Challenges and opportunities in molecular imaging involving drug discovery, validation, intellectual property in licensing and regulatory compliance are discussed.

A positron emission tomography (PET) for animals using cadmium telluride (CdTe) detectors was developed for the purpose of biomedical study using rats and mice. The spatial resolution of 0.8mm FWHM within the central 20 mm-diameter of field of view (FOV) was obtained by the use of small CdTe elements of 1.1 mm 1.0 mm 5 mm. The FOV is 64 mm in diameter and 26 mm in axis. Fine images were successively obtained following [18F]fluorodeoxyglucose ([18F]FDG) injection to a rat and a mouse. In the fine [18F]FDG images, the cerebral cortex, the gray matter and the corpus striatum was able to be respectively distinguished.

Progressive deposition of amyloid plaques in the brain, which begins before the appearance of cognitive decline, is an initiating event in the pathogenesis of Alzheimer's disease. Therefore, noninvasive detection of amyloid pathology is important for presymptomatic diagnosis and preventive therapy for Alzheimer's disease. Recent research advances have enabled the in vivo imaging of amyloid pathology in humans using nuclear medicine technology. Several amyloid-binding agents have been developed and evaluated by positron emission tomography (PET) and single photon emission computed tomography (SPECT) for their use as contrast agents. Available clinical evidence indicates that amyloid imaging enables the early diagnosis of Alzheimer's disease with high accuracy and suggests its usefulness for the prediction of progression to Alzheimer's disease in subjects with mild cognitive impairment and probably also in cognitively normal individuals. Another application of this technology is as a surrogate marker for monitoring brain amyloid. In this review, we describe recent progress in the development of amyloid imaging technology and human clinical trials.

Combined positron emission tomography (PET) or single photon emission computed tomography (SPECT) with computed tomography (CT) has been rapidly developed because of unique physiological information benefits from a precise topographic localization. PET/CT has been more accurate that anatomical imaging for diagnosing, staging, restaging and assessing therapeutic responses in a large number of different cancers. SPECT/CT has been somewhat overlooked since the procedures with single-photon tracers still constitute the majority of everyday nuclear medicine practice. Besides of precise localization of the lesions CT findings also characterize the abnormalities. Many existing and potential areas of clinical applications as well as translational researches using PET/CT and SPECT/CT are briefly reviewed.