Radiopharmaceuticals For Molecular Imaging Research Articles

Total Radiosynthesis: Thinking outside "the box".

The logic of total synthesis transformed a stagnant state of medicinal and synthetic organic chemistry when there was a paucity of methods and reagents to synthesize drug molecules and/or natural products. Molecular imaging by positron emission tomography (PET) is now experiencing a renaissance in the way radiopharmaceuticals for molecular imaging are synthesized, however, a paradigm shift is desperately needed in the discovery pipeline to accelerate in vivo imaging studies. A significant challenge in radiochemistry is the limited choice of labeled reagents (or building blocks) available for the synthesis of novel radiopharmaceuticals with the most commonly used short-lived radionuclides carbon-11 (11C; half-life ~20 minutes) and fluorine-18 (18F; half-life ~2 hours). In fact, most drugs cannot be labeled with 11C or 18F due to a lack of efficient and diverse radiosynthetic methods. In general, routine radiopharmaceutical production relies on the incorporation of the isotope at the last or penultimate step of synthesis, ideally within one half-life of the radionuclide, to maximize radiochemical yields and specific activities thereby reducing losses due to radioactive decay. Reliance on radiochemistry conducted within the constraints of an automated synthesis unit ("box") has stifled the exploration of multi-step reactions with short-lived radionuclides. Radiopharmaceutical synthesis can be transformed by considering logic of total synthesis to develop novel approaches for 11C- and 18F-radiolabeling complex molecules via retrosynthetic analysis and multi-step reactions. As a result of such exploration, new methods, reagents and radiopharmaceuticals for in vivo imaging studies are discovered. A new avenue to develop radiotracers that were previously unattainable due to the lack of efficient radiosynthetic methods is necessary to work towards our ultimate, albeit impossible goal - the concept we term total radiosynthesis - to radiolabel virtually any molecule. As with the vast majority of drugs, most radiotracers also fail, therefore expeditious evaluation of tracers in preclinical models prior to optimization or derivatization of the lead molecules/drugs is necessary. Furthermore the exact position of the 11C and 18F radionuclide in tracers is often critical for metabolic considerations, and flexible methodologies to introduce the radiolabel are needed. Using the principles of total synthesis our laboratory and others have shown that multi-step radiochemical reactions are indeed suitable for preclinical and even clinical use. As the goal of total synthesis is to be concise, we have also simplified the syntheses of radiopharmaceuticals. We are presently developing new strategies via [11C]CO2 fixation which has enabled library radiosynthesis as well as labeling non-activated arenes using [18F]fluoride via iodonium ylides. Both of which have proven to be suitable for human PET imaging. We concurrently utilize state-of-the-art automation technologies including microfluidic flow chemistry and rapid purification strategies for radiopharmaceutical production. In this account we highlight how total radiosynthesis has impacted our radiochemistry program, with prominent examples from others, focusing on its impact towards preclinical and clinical research studies.

Editorial (Thematic Issue: Current Status and Progress of Radiopharmaceuticals for Molecular Imaging and Targeted Therapy)

Editorial (Thematic Issue: Current Status and Progress of Radiopharmaceuticals for Molecular Imaging and Targeted Therapy)

IAEA Support to Medical Physics in Nuclear Medicine

Through its programmatic efforts and its publications, the International Atomic Energy Agency (IAEA) has helped define the role and responsibilities of the nuclear medicine physicist in the practice of nuclear medicine. This paper describes the initiatives that the IAEA has undertaken to support medical physics in nuclear medicine. In 1984, the IAEA provided guidance on how to ensure that the equipment used for detecting, imaging, and quantifying radioactivity is functioning properly (Technical Document [TECDOC]-137, "Quality Control of Nuclear Medicine Instruments"). An updated version of IAEA-TECDOC-137 was issued in 1991 as IAEA-TECDOC-602, and this included new chapters on scanner-computer systems and single-photon emission computed tomography systems. Nuclear medicine physics was introduced as a part of a project on radiation imaging and radioactivity measurements in the 2002-2003 IAEA biennium program in Dosimetry and Medical Radiation Physics. Ten years later, IAEA activities in this field have expanded to cover quality assurance (QA) and quality control (QC) of nuclear medicine equipment, education and clinical training, professional recognition of the role of medical physicists in nuclear medicine physics, and finally, the coordination of research and development activities in internal dosimetry. As a result of these activities, the IAEA has received numerous requests to support the development and implementation of QA or QC programs for radioactivity measurements in nuclear medicine in many Member States. During the last 5 years, support was provided to 20 Member States through the IAEA's technical cooperation programme. The IAEA has also supported education and clinical training of medical physicists. This type of support has been essential for the development and expansion of the Medical Physics profession, especially in low- and middle-income countries. The need for basic as well as specialized clinical training in medical physics was identified as a priority for healthcare providers in many countries. The IAEA's response to meet the increasing needs for training has been 2-folds. Through its regular program, a priority is given to the development of standardized syllabi and education and clinical training guides. Through its technical cooperation programme, support is given for setting up national medical physics education and clinical training programs in countries. In addition, fellowships are granted for professionals working in the field for specialized training, and workshops are organized at the national and regional level in specialized topics of nuclear medicine physics. So as to support on-the-job training, the IAEA has also setup a gamma camera laboratory in Seibersdorf, Austria. The laboratory is also equipped with QC tools and equipments, and radioisotopes are procured when training events are held. About 2-3 specialized courses are held every year for medical physicists at the IAEA gamma camera laboratory. In the area of research and development, the IAEA supports, through its coordinated research projects, new initiatives in quantitative nuclear medicine and internal dosimetry. The future of nuclear medicine is driven by advances in instrumentation, by the ever increasing availability of computing power and data storage, and by the development of new radiopharmaceuticals for molecular imaging and therapy. Future developments in nuclear medicine are partially driven by, and will influence, nuclear medicine physics and medical physics. To summarize, the IAEA has established a number of programs to support nuclear medicine physics and will continue to do so through its coordinated research activities, education and training in clinical medical physics, and through programs and meetings to promote standardization and harmonization of QA or QC procedures for imaging and treatment of patients.

Radiopharmaceuticals for Molecular Imaging

Radiopharmaceuticals for molecular imaging involve careful consideration of the following two factors: radionuclide selection and specificity to the molecular target. In selecting a radionuclide, the specific decay mode, physical half-life, chemical properties, and method of production must be considered. For proper design of a radiopharmaceutical which targets a specific biological or disease process, structural features, including the size, charge, solubility, lipophilicity, and specific activity of the radiolabeled molecules, must be considered. Other factors, such as the rate of metabolism, plasma protein binding, and non-specific binding in non-target tissues, are also important in optimizing the in vivo behavior of radiolabeled molecules. There are several types of radiopharmaceuticals for molecular imaging that target a number of biochemical processes, such as blood flow or perfusion, metabolism, and specific receptors. With a better understanding of the properties of radiopharmaceuticals, including chemical, physical, and biological properties, radiopharmaceuticals can be properly used for molecular imaging of targets for biological or disease processes.

Biokinetics and dosimetry of target-specific radiopharmaceuticals for molecular imaging and therapy

Molecular imaging techniques directly or indirectly monitor and record the spatiotemporal distribution of molecular or cellular processes for biochemical, biologic, diagnostic or therapeutic applications. 99mTc-HYNIC-TOC has shown high stability both in vitro and in vivo and rapid detection of somatostatin receptor-positive tumors. Therapies using radiolabeled anti-CD20 have demonstrated their efficacy in patients with B-cell non-Hodgkin's lymphoma (NHL). The aim of this study was to establish biokinetic models for 99mTc-HYNIC-TOC and 188Re-anti-CD20 and to evaluate their dosimetry as target-specific radiopharmaceuticals. The OLINDA/EXM code was used to calculate patient-specific internal radiation dose estimates. 99mTc-HYNIC-TOC images showed an average tumor/blood ratio of 4.3±0.7 in receptor-positive tumors with an average effective dose of 4.4 mSv. Dosimetric studies indicated that after administration of 5.8 to 7.5 GBq of 188Re-anti-CD20 the absorbed dose to total body would be 0.75 Gy which corresponds to the recommended dose for NHL therapies.