Radionuclides and radiopharmaceuticals for single-photon emission tomography, positron emission tomography and radiotherapy in Russia.

The current status of the manufacture of radiopharmaceuticals for diagnostic and therapeutic application in Russia is discussed, consideration being given to various aspects of the production and distribution of radionuclides, radioisotope generators and kits as well as individual radiopharmaceuticals in different regions of the country. The major focus is on the recent developments in production technologies for therapeutic and single-photon emission tomography radionuclides, technetium chemistry and synthetic approaches for the labelling of compounds with short-lived positron emitters. The status of positron emission tomography and its application are considered. The major factors restricting the expansion of nuclear imaging techniques and radiotherapy in Russia are also discussed.     

Cyclotrons and positron emission tomography radiopharmaceuticals for clinical imaging

Positron emission tomography (PET) requires positron-emitting radionuclides that emit 511-keV photons detectable by PET imagers. Positron-emitting radionuclides are commonly produced in charged particle accelerators, eg, linear accelerators or cyclotrons. The most widely available radiopharmaceuticals for PET imaging are carbon-11-, nitrogen-13-, and oxygen-15-labeled compounds, many of which, either in their normal state or incorporated in other compounds, serve as physiological tracers. Other useful PET radiopharmaceuticals include fluorine-18-, bromine-75-, gallium-68 (68Ga)-, rubidium-82 (82Rb)-, and copper-62 (62Cu)-labeled compounds. Many positron emitters have short half-lives and thus require on-site cyclotrons for application, and others (68Ga, 82Rb, and 62Cu) are available from radionuclides generators using relatively long-lived parent radionuclides. This review is divided into two sections: cyclotrons and PET radiopharmaceuticals for clinical imaging. In the cyclotron section, the principle of operation of the cyclotron, types of cyclotrons, medical cyclotrons, and production of radionuclides are discussed. In the section on PET radiopharmaceuticals, the synthesis and clinical use of PET radiopharmaceuticals are described.     

Alternative positron emission tomography with non-conventional positron emitters: effects of their physical properties on image quality and potential clinical applications

The increasing amount of clinically relevant information obtained by positron emission tomography (PET), primarily with fluorine-18 labelled 2-deoxy-2-fluoro-d-glucose, has generated a demand for new routes for the widespread and cost-efficient use of positron-emitting radiopharmaceuticals. New dual-head single-photon emission tomography (SPET) cameras are being developed which offer coincidence detection with camera heads lacking a collimator or SPET imaging with specially designed collimators and additional photon shielding. Thus, not only satellite PET imaging units but also nuclear medicine units investing in these new SPET/PET systems need to examine all available alternatives for rational radionuclide supplies from host cyclotrons. This article examines 25 ”alternative” positron-emitting radionuclides, discusses the impact of their decay properties on image quality and reviews methods for their production as well as for their application in imaging techniques.     

Needs for radioactivity standards and measurements in the life sciences.

For almost 100 years, radioactivity has been one of the major tools in medicine. Therapeutic applications that began with 226Ra and 222Rn implants have rapidly grown to include about 20 radionuclides with radiations specifically chosen to treat at different depths in tissue--ranging from a few millimeters for intravascular therapy to a few centimeters in the case of large solid tumors. Systemic treatments with radiopharmaceuticals have grown from the traditional 131I to more than ten candidate nuclides which are to be labeled to tumor-specific radiopharmaceuticals. Diagnostic radiopharmaceuticals are used in over 13 million procedures in the United States annually. About 40 nuclides are under investigation for these applications including single photon emitters for SPECT (single photon emission computed tomography) and positron emitters for PET (positron emission tomography). In addition to the mainstays of therapeutic and diagnostic radiology, radionuclides are widely used for in vitro tracers in the life sciences and represent one of the main tools in the field of molecular biology.     

Positron emission tomography: a technical introduction for clinicians

Up to a few years ago, positron emission tomography (PET) was known as a very expensive research tool using positron emitting radiopharmaceuticals to study metabolic processes in vivo. Recent developments in detector technology enabled the detection of the distribution of positron emitting radionuclides inside the human body through dual-headed gamma camera systems. These much cheaper cameras did move the focus of PET from research to clinical applications. The improved availability of [(18)F]fluorodeoxyglucose has promoted clinical PET. Ongoing developments in detector and image reconstruction technology may lead to even more accurate imaging in the clinical setting. New applications in diagnosing and staging of cancer patients came across and more will arise. In this paper, we present a short historical overview and a technical introduction of PET.     

Conventional radionuclide brain imaging in the era of transmission and emission tomography

The clinical applications for conventional radionuclide brain imaging have declined considerably since the introduction of newer imaging modalities (computerized cranial tomography [CCT], nuclear magnetic resonance [NMR]). Currently, conventional brain imaging primarily serves as a complementary test when CCT is negative or equivocal and strong clinical suspicion remains. Selected areas in which radionuclide imaging may be the preferred modality include evaluation of cerebral perfusion in assessment of brain death, detection of early viral encephalitis, evaluation of major venous sinus patency, external marking for localization of intracranial tumor, and in selected cases of suspected subdural hematoma, brain tumor, and cerebrovascular disease. The concept of conventional radionuclide brain imaging will likely undergo considerable change in the near future as newer radiopharmaceuticals are introduced and wider application is made of single photon emission computerized tomography (SPECT) and positron emission tomography (PET) imaging.     

The next generation of positron emission tomography radiopharmaceuticals in oncology

Although (18)F-fluorodeoxyglucose ((18)F-FDG) is still the most widely used positron emission tomography (PET) radiotracer, there are a few well-known limitations to its use. The last decade has seen the development of new PET probes for in vivo visualization of specific molecular targets, along with important technical advances in the production of positron-emitting radionuclides and their related labeling methods. As such, a broad range of new PET tracers are in preclinical development or have recently entered clinical trials. The topics covered in this review include labeling methods, biological targets, and the most recent preclinical or clinical data of some of the next generation of PET radiopharmaceuticals. This review, which is by no means exhaustive, has been separated into sections related to the PET radionuclide used for radiolabeling: fluorine-18, for the labeling of agents such as FACBC, FDHT, choline, and Galacto-RGD; carbon-11, for the labeling of choline; gallium-68, for the labeling of peptides such as DOTATOC and bombesin analogs; and the long-lived radionuclides iodine-124 and zirconium-89 for the labeling of monoclonal antibodies cG250, and J591 and trastuzumab, respectively.     

Copper radionuclides and radiopharmaceuticals in nuclear medicine

The chemistry, radiochemistry, radiobiology, and radiopharmacology of radiopharmaceuticals containing copper radionuclides are reviewed. Copper radionuclides offer application in positron emission tomography, targeted radiotherapy, and single photon imaging. The chemistry of copper is relatively simple and well-suited to radiopharmaceutical application. Current radiopharmaceuticals include biomolecules labelled via bifunctional chelators primarily based on cyclic polyaminocarboxylates and polyamines, and pyruvaldehyde-bis(N⁴-methylthiosemicarbazone) (PTSM) and its analogues. The chemistry of copper, of which only a fraction has yet been exploited, is likely to be applied more fully in the future.     

Cost analyses of positron emission tomography for clinical use

Costs associated with the clinical use of positron emission tomography (PET) at the Mallinckrodt Institute of Radiology are analyzed according to the two major components: radiopharmaceutical production and imaging. Estimated annual costs are +584,500 for PET radiopharmaceutical production and +644,250 for PET imaging (1982 U.S. dollars). The economic break-even point charge to cover expenses is +615-+2,780 per clinical procedure, depending on several variables, especially procedure volume. Charges for PET clinical procedures will be among the highest of all charges for diagnostic imaging procedures, perhaps even higher than these estimates at some institutions. Several technologic and procedural approaches to reducing costs are suggested, the most promising being the anticipated availability of positron-emitting radionuclides from commercial suppliers.     

Positron emission tomography of the brain

Positron emission tomography (PET) is a technique of transverse tomographic imaging in which detection of two photons emitted from the annihilation of a positron and an electron is used to reconstruct the distribution of a positron emitting isotope within an object. PET provides the capacity to quantitatively measure the local tissue distribution of a variety of radionuclides that are attached to compounds that distribute according to function. Although this technique has been used to measure multiple functions and receptors within the brain, one of the most widespread uses is the measurement of local cerebral glucose metabolism based on the deoxyglucose method. In this article, the application of PET to clinical disorders such as dementia, brain tumors, psychiatric disease, epilepsy, movement disorders, and stroke as well as to normal states such as aging are examined.     

Radiobromine-labelled tracers for positron emission tomography: possibilities and pitfalls

The use of positron emission tomography (PET) for radionuclide imaging provides better sensitivity, better spatial and temporal resolution and better quantification accuracy in comparison with single photon emission computed tomography (SPECT). One limitation of PET is the predominant use of short-lived (with half-life up to 2 h) radionuclides. Extension of PET utility might be achieved by the use of more long-lived, "non-conventional" positron emitters. Two positron-emitting isotopes of bromine, 75Br (T1/2 = 96.7 min) and 76Br (T1/2 = 16.2 h), can be considered as labels for targeting proteins and peptides, and for small molecules, which have an optimal imaging time outside the time frame provided by conventional biogenic positron emitters. Variety of tracers might be labelled by electrophilic bromination of activated phenolic rings, electrophilic bromodestannylation and halogen exchange. A major problem is that in vivo metabolism of tracers might lead to formation of radiobromide as a main radiocatabolite. Radiobromide is very slowly excreted, and is distributed in the extracellular space creating high background. Careful tracer design optimisation is required to avoid this obstacle in the introduction of bromine isotopes into PET practice.     

(68)Ga-labeled DOTA-peptides and (68)Ga-labeled radiopharmaceuticals for positron emission tomography: current status of research, clinical applications, and future perspectives

In this review we give an overview of current knowledge of (68)Ga-labeled pharmaceuticals, with focus on imaging receptor-mediated processes. A major advantage of a (68)Ge/(68)Ga generator is its continuous source of (68)Ga, independently from an on-site cyclotron. The increase in knowledge of purification and concentration of the eluate and the complex ligand chemistry has led to (68)Ga-labeled pharmaceuticals with major clinical impact. (68)Ga-labeled pharmaceuticals have the potential to cover all today's clinical options with (99m)Tc, with the concordant higher resolution of positron emission tomography (PET) in comparison with single photon emission computed tomography. (68)Ga-labeled analogs of octreotide, such as DOTATOC, DOTANOC, and DOTA-TATE, are in clinical application in nuclear medicine, and these analogs are now the most frequently applied of all (68)Ga-labeled pharmaceuticals. All the above-mentioned items in favor of successful application of (68)Ga-labeled radiopharmaceuticals for imaging in patients are strong arguments for the development of a (68)Ge/(68)Ga generator with Marketing Authorization and thus to provide pharmaceutical grade eluate. Moreover, now not one United States Food and Drug Administration-approved or European Medicines Agency-approved (68)Ga-radiopharmaceutical is available. As soon as these are achieved, a whole new radiopharmacy providing PET radiopharmaceuticals might develop.     

Evaluation of coronary artery disease with positron emission tomography

Positron emission tomography (PET) represents the most sophisticated imaging modality in nuclear medicine allowing quantification of regional tracer tissue concentrations. Beside the technical superiority of data acquisition, a large number of PET radiopharmaceuticals are available for clinical application. Based on currently available data, PET provides detection of coronary artery disease with higher diagnostic accuracy than conventional thallium-201 single positron emission computed tomography. Applications of PET with metabolic tracers have been shown to provide clinically important information in the management of patients with advanced coronary artery disease. Metabolic tissue characterization represents the most specific definition of tissue viability currently available. However, the relatively high cost of the technology and the lack of reimbursement by major insurance carriers has limited widespread clinical application. In addition to the acceptance of PET as an advanced clinical imaging modality, this imaging modality excels as a sophisticated research tool assessing specific tissue functions that could not be visualized before in the living human heart. Without doubt, this technique will contribute significantly to the future characterization of pathophysiological alterations in substrate metabolism and other physiological processes such as autonomic innervation. Furthermore, the kinetics of radiolabeled cardiac drugs may be studied with PET to provide objective characterization of cardiovascular drug effects and thus enhance our understanding of pharmacokinetics in the human heart.     

Optimized scintigraphic evaluation of infection and inflammation: role of single-photon emission computed tomography/computed tomography fusion imaging

Gallium-67 citrate and radiolabeled white blood cells have become standard inflammation/infection-seeking agents whereas other agents, such as (99m)Tc diphosphonates, commonly are used to infer an infectious process. These radiopharmaceuticals reflect physiologic and pathologic function rather than anatomical abnormality. In the clinical setting, it is often necessary to correlate these functional studies with anatomical imaging. The advent of single-photon emission computed tomography, as well as positron emission tomography, provides tomographic images for direct correlation to anatomic modalities such as computed tomography and magnetic resonance imaging. The methods by which these functional and anatomic imaging modalities are correlated include side-by-side, software, and hardware fusion. Clinically, fusion imaging has been applied primarily to oncologic and neurologic applications. The literature supports the premise that multimodality fusion would increase the specificity of the physiologic modality and increase the sensitivity of the anatomic modality. Our institution uses software fusion to aid in the diagnosis of infection and inflammation. Through case vignettes, we illustrate applications for single-photon emission computed tomography/computed tomography fusion for the diagnosis of infection and inflammation in multiple organ systems.     

Radiopharmaceuticals for renal positron emission tomography imaging

Radiopharmaceuticals for functional renal imaging, including renal blood flow, renal blood volume, glomerular excretion, and metabolism have been available for some time. This review outlines radiopharmaceuticals for functional renal imaging as well as those that target pertinent molecular constituents of renal injury and repair. The angiotensin and endothelin receptors are particularly appealing molecular targets for renal imaging because of their association with renal physiology and pathology. Other targets such as the vascular endothelial growth factor (VEGF) receptor, integrin, or phosphatidylserine have been investigated at length for cancer imaging, but they are just as important constituents of the renal injury/repair process. Various diseases can involve identical mechanisms, such as angiogenesis and apoptosis, and radiopharmaceuticals developed for these processes in other organs can also be used for renal imaging. The sensitivity and spatial resolution of positron emission tomography makes it an ideal tool for molecular and functional kidney imaging. Radiopharmaceutical development for the kidneys must focus on achieving high target selectivity and binding affinity, stability and slow metabolism in vivo, and minimal nonspecific accumulation and urinary excretion.     

Brain tumour recurrence: brain single-photon emission computerized tomography, PET and proton magnetic resonance spectroscopy

Recurrence is a frequent clinical problem in the follow-up of brain tumours. Single-photon emission computerized tomography, positron emission tomography (PET) and proton magnetic resonance spectroscopy (1H-MRS) represent significant diagnostic options to investigate recurrence. Many authors studied the separate and associate significance of these modalities in investigating relapsing brain tumours. In this study, the current role and the perspectives of these functional diagnostic tools are presented, evidencing the valuable results provided by their association. Finally, future development of new radiopharmaceuticals and advanced MRS technique can reliably contribute to improve the diagnostic process of recurrent brain neoplasms.     

Studies of central nervous system disorders with single photon emission computed tomography and positron emission tomography: evolution over the past 2 decades

Single photon emission computed tomography (SPECT) was introduced in the 1960s to detect breakdowns in the blood-brain barrier and was replaced by x-ray computed tomography in the mid-1970s. The development of the deoxyglucose (DG) technique to measure regional cerebral glucose metabolism by employing either autoradiography, using 14CDG, or positron emission tomography (PET), using 18FDG, added a major dimension to the investigation of brain function. In the late 1970s and early 1980s, the FDG-PET technique was widely used to examine a variety of neuropsychiatric disorders. It soon became apparent that functional imaging was more sensitive than anatomic imaging in detecting abnormalities of the brain related to aging, dementia, tumors, seizures, cerebral vascular accidents, and psychiatric problems. Because of its complexity and the cost involved, PET was used in a limited number of centers in the United States. However, the success of PET resulted in the resurgence of interest in SPECT as an alternative technology after almost a decade. This became possible because of the synthesis of iodine 123- and technetium 99m-labeled radiopharmaceuticals to determine regional cerebral blood flow. Since blood flow and metabolism are coupled in most pathological states, patterns of abnormality noted on SPECT were similar to those seen on PET in many disorders. Since the introduction of high resolution SPECT imaging instruments, the role of SPECT has been further enhanced. The successful synthesis of both positron and single emitting radioligands to image dopamine and other receptors has started a new era in neurosciences and will have a far-reaching impact on the day-to-day practice of neuropsychiatry.     

The search for consistency in the manufacture of PET radiopharmaceuticals

Nuclear Medicine is the specialty of medical imaging, which utilizes a variety of radionuclides incorporated into specific compounds for diagnostic imaging and therapeutic applications. During recent years, research efforts in this discipline have concentrated on the decay characteristics of particular radionuclides and the design of unique radiolabeled tracers necessary to achieve time-dependent molecular images. Various oncology applications have utilized specific PET and SPECT radiopharmaceuticals, which have allowed an extension from functional process imaging in tissue to pathologic processes and nuclide directed treatments. One of the most widely recognized advantages of positron emission tomography (PET) is its use of the attractive, positron-emitting biologic radiotracers that mimic natural substrates. However, a major disadvantage is that these substances are relatively short-lived and unable to be transported great distances. At this time, economic considerations and regulatory guidelines associated with the creation of a PET facility, as well as the operational costs of maintaining both the facility and the necessary procedural documentation, continue to create interesting strategic dilemmas. This commentary will focus on the current approach and anticipated impact of pending regulations, which relate to the manufacture and formulation of a variety of PET radiopharmaceuticals used in clinical research and patient management at Memorial Hospital.     

Development of a high performance zinc-62/copper-62 radionuclide generator for positron emission tomography.

Clinical utilisation of positron emission tomography could be enhanced by the availability of short-lived radionuclides derived from generator systems. The zinc-62/copper-62 combination is one such system which could be used as a source for a number of copper-62 radiopharmaceuticals. We have developed and optimised a high activity (5.6 GBq, 150 mCi) zinc-62/copper-62 generator to provide 62Cu in a form that is suitable for direct labelling of pyruvaldehyde-bis-(N4-methylthiosemicarbazone)-copper(II), Cu(PTSM). The distribution coefficients of Zn(II) and Cu(II) between anion-exchange resin and various hydrochloric acid/organic solvent mixtures were measured. Based on these measurements a generator eluent of 0.3 M HCl/40% ethanol provided 62Cu in greater than 90% yield in a 3-ml volume. A very low 62Zn breakthrough of less than 3 x 10(-7)% was achieved. Copper-PTSM was successfully labelled with the no-carrier-added 62Cu eluent directly from the generator with 94% radiochemical yield.     

Fluorinated amino acids for tumour imaging with positron emission tomography

The currently preferred radiopharmaceutical for positron emission tomography (PET) in oncology is 2-[(18)F]fluoro-deoxyglucose (FDG). Increased accumulation of this deoxyglucose analogue in tumour cells is based on elevated glucose metabolism by tumour cells and subsequent trapping in the cells. In the search for new PET tracers, amino acids have been widely studied. A new amino acid tracer should preferably have similar high uptake in tumour cells but low non-specific uptake in normal tissues and any pathology other than tumour. In recent years, several amino acids have been labelled with either gamma radiation-emitting radionuclides or positron-emitting radionuclides, the most commonly used being carbon-11. However, the longer half-life of fluorine-18 matches better with the relatively slow process of protein synthesis and also facilitates shipping of the radiolabelled amino acids to hospitals without an on-site cyclotron or dedicated radiochemistry laboratory. The number of fluorinated amino acids under investigation is increasing, and one of the major points of discussion is the underlying mechanism of the tumour visualisation. While it has been shown that some amino acids can be used to measure the protein synthesis rate, others are used with the sole aim of measuring the rate of uptake into the cell. The differences between measuring amino acid transport (rate) and protein synthesis rate with (18)F-labelled amino acids are discussed.