Positron Emission Tomography Radiopharmaceuticals Research Articles

Metabolic imaging with FDG: a primer.

The rapid advances in imaging technologies are a challenge for both radiologists and clinicians who must integrate these technologies for optimal patient care and outcomes at minimal cost. Multiple indications for functional imaging using fluorode-oxyglucose (FDG) are now well accepted in the fields of neurology, cardiology, and oncology, including differentiation of benign from malignant lesions, staging of malignant lesions, detection of malignant recurrence, and monitoring of therapy. The fusion of anatomic and molecular images (computed tomography [CT] and FDG) obtained with integrated positron emission tomography (PET)-CT systems, sequentially in time but without moving the patient from the imaging table, allows optimal co-registration of anatomic and molecular images, leading to accurate attenuation correction and precise anatomic localization of lesions with increased metabolism. This powerful technology provides a valuable new tool for diagnostic and therapeutic applications. The diagnostic accuracy is improved in approximately 50% of patients because of improvement of lesion detection on both CT and FDG PET images, better differentiation between physiologic and pathological foci of FDG uptake, and better localization of malignant foci of FDG uptake. This new technology affects the management of 10%-20% of cases by guiding further therapy. Promising clinical applications include guiding biopsy to the metabolically active sites of tumors, guiding surgery, and planning intensity-modulated radiation therapy. In addition, new PET radiopharmaceuticals are emerging for indications for which FDG has limitations. Some of the new PET tracers are labeled with (18)F, which has a practical half-life for commercial distribution. In the past few years, the clinical indications for FDG have broadened dramatically, and the rapid technical developments of integrated multimodality imaging systems and new PET tracers further extend the horizon.

Clinical PET Imaging – An Asian Perspective

Positron emission tomography (PET) has entered a new phase of development since a major technological breakthrough in 2000. Combined with computed tomography (CT), the second-generation PET-CT scanner is now able to obtain both functional and anatomical information of the whole body from a single study. Its application in oncology has become one of the standard imaging modalities in diagnosis, staging and monitoring therapeutic efficacy. It is well known that the Asian and Western populations have their own characteristic disease spectrum and cancer incidence. Although changes in diet and life-style have narrowed the differences in the last decade, there remains moderate divergence and disparities in cancer pattern and priority of resource allocation in different countries. It is known that F-18 fluorodeoxyglucose (FDG) is the most widely used radiopharmaceutical in PET imaging and it has been confirmed valuable in a variety of cancer types such as lung, colorectum, oesophagus, head and neck (including nasopharyngeal carcinoma), breast, pancreas, lymphoma, melanoma, cholangiocarcinoma and many types of sarcoma. Some cancer types, however, are less sensitive to FDG-PET detection and these include hepatocellular carcinoma, urological carcinoma, gastric malignancy, mucinous and clear-cell gastrointestinal tumours, neuroendocrine tumours and well-differentiated thyroid cancers. Some of these less sensitive cancer types are more prevalent in the Asian population than the Euro-American population and are, therefore, more frequently encountered as false negative cases in FDG-PET imaging. On the other hand, Asian countries are more prevalent in diseases such as tuberculosis and the chance of having false positive FDG-PET cases is higher than the Euro-American countries in the evaluation of lung and other cancers. From the Asian perspective, we are more susceptible to having a higher chance of both false negative and false positive FDG-PET cases. Thus, there is a stronger emphasis of research on new drugs to overcome the limitations of FDG. The use of PET imaging as a diagnostic tool has gained wide acceptance in Asia during the past few years and its clinical utility is expected to continue to rise. More research on other PET radiopharmaceuticals should therefore be given a higher priority along side with the maturation of scanning technology.

PET radiopharmaceuticals for metabolic imaging in oncology

Early detection is critical to successful treatment and long-term cure of cancer. Detection relies on a broad array of mutually supporting diagnostic modalities, including visual detection of superficial lesions, quantification of biological and metabolic markers, and noninvasive imaging. The advantage of imaging techniques over circulating markers is that imaging defines the precise location of the tumor. Of the imaging techniques available today, positron emission tomography (PET) offers the best combination of selectivity, specificity, and sensitivity when used with appropriate molecular radiopharmaceuticals. In addition, PET images can be analyzed to provide quantitative kinetic data (parametric imaging) and biochemical knowledge at physiological molecular concentrations. This information is invaluable in staging, therapy planning, and therapeutic monitoring of cancer. Bioenergetics, genomics, and proteomics present unique opportunities to study and characterize cell growth and proliferation using PET. 2-[ 18F]FDG, a probe of one component of cellular glycolysis, is the major PET tracer used in clinical oncology today. However, the potential contributions of PET to oncology extend well beyond 2-[ 18F]FDG and other F-18-labeled tracers. Chemical classes of PET radiotracers commonly used in preclinical and clinical experimental oncology include carbohydrates, fatty acids, nucleosides, oligonucleotides, nitroimidazoles, amino acids, peptides, proteins, and antibodies. Fluorine-18, C-11, and radiometals are the most frequently used radionuclides. These PET radiopharmaceuticals are useful in the assessment of tissue bioenergetics, hypoxia, proliferation, and function. The following paragraphs present an overview of hexose-based measurement of glucose metabolism as an indicator of tumor viability, and nitroimidazole-based compounds as markers of regional tissue hypoxia, using PET. Emphasis is placed on the use of [ 18F]-fluorodeoxyglucose (FDG) and [ 18F] fluoroazomycin arabinoside (FAZA) in oncology.

Potential and Practical Adrenomedullary PET Radiopharmaceuticals as an Alternative to m-Iodobenzylguanidine: m-(ω-[18F]Fluoroalkyl)benzylguanidines

To investigate adrenomedullary radiopharmaceuticals for positron emission tomography (PET), we have developed no-carrier-added m-(omega-[18F]fluoroalkyl)benzylguanidines. m-(omega-[18F]Fluoroalkyl)benzylguanidines were prepared in two steps starting from N,N'-bis(tert-butyloxycarbonyl)-N' '-(omega-methanesulfonyloxyalkyl)benzylguanidines in 20-30% radiochemical yields (decay corrected for 100 min) and with high radiochemical purity (>97%) and shown to be stable (>90%) in an in vitro metabolic stability assay. The binding of m-(3-[18F]fluoropropyl)benzylguanidine ((18F]3) to SK-N-SH human neuroblastoma cells was temperature dependent, and binding levels at 4 degrees C were reduced to half of that at 37 degrees C, which was similar to the reduction rate observed for [123I]MIBG. Tissue distribution studies in mice showed the highest uptake in the adrenals (%ID/g = 27.2 +/- 5.0%) with relatively high uptake in the myocardium (%ID/g = 9.3 +/- 0.5%). The results suggest that this radiotracer holds promise as a useful adrenomedullary radiopharmaceutical for PET imaging.

Visualizing protein–protein interactions in living animals

A variety of techniques have been developed to analyze protein–protein interactions in vitro and in cultured cells. However, these methods do not determine how protein interactions affect and are regulated by physiologic and pathophysiologic conditions in living animals. This article describes methodology for detecting and quantifying protein interactions in living mice, using an inducible two-hybrid system developed for positron emission tomography (PET) imaging. We discuss the methods to establish stably transfected cells with components of the imaging system, create tumor xenografts, synthesize PET radiopharmaceuticals used to visualize the imaging reporter, perform microPET imaging, and analyze data from imaging studies. Development and application of technologies for molecular imaging of protein–protein interactions in vivo should enable researchers to investigate intrinsic binding specificities of proteins during normal development and disease progression as well as aid drug development through direct interrogation of molecular targets within intact animals.

A Fully Automated One Pot Synthesis of 9-(4-[ 18F]Fluoro-3-Hydroxymethylbutyl) Guanine for Gene Therapy Studies

Purpose: To develop a new fully-automated method for the synthesis of 9-(4-[ 18F]fluoro-3-hydroxymethylbutyl)guanine ([ 18F]FHBG) amenable for its routine use in gene therapy monitoring studies. Procedures: A nuclear interface commercial synthesizer was substantially modified and adapted to the synthesis of the referred compound. After the fluorination reaction of the tosylate precursor, the intermediate product was purified by Solid Phase Extraction (SPE) before the hydrolysis. The final product was purified by semi-preparative high performance liquid chromatography (HPLC). Results: [ 18F]FHBG was obtained in 10–15% yield in 65 minutes including HPLC purification. The radiotracer was > 99% chemically and radiochemically pure, sterile and free from pyrogens. The synthesized compound was shown to accumulate in thymidine kinase (tk) expressing cells both in cell culture, and in laboratory animals infected with an adenoviral vector containing the herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene. Conclusions: This new procedure facilitates the compliance with the applicable regulatory guidelines for positron emission tomography (PET) radiopharmaceuticals and will assist the clinical application of [ 18F]FHBG-PET as a noninvasive way to monitor gene therapy in humans.

A survey of PET activity in Germany during 1999

Positron emission tomography (PET) is the most powerful molecular imaging technique currently available for clinical use. The aim of this study was to provide public health information on PET procedures carried out in Germany - a country with a very high number of PET installations. To this end, all facilities that in 1999 were running at least one dedicated PET system were contacted and requested to provide information in a questionnaire on the radiopharmaceuticals applied, the total number and age distribution of patients and volunteers examined, the main diagnostic applications and the range of administered activities. Based on the information provided by 48 of the 60 PET facilities in Germany, an annual frequency of about 0.34 PET procedures per 1,000 inhabitants was estimated, associated with an annual per capita effective dose of about 1.9 micro Sv. Averaged over all PET procedures, the mean effective dose to patients was 5.6 mSv. The age distribution of patients and volunteers was skewed markedly towards higher ages; only a very small fraction (<3%) of patients were children younger than 15 years while older patients, and especially those in the age group between 41 and 65 years, were overrepresented relative to the general population. In total, 28 different PET radiopharmaceuticals were used, with only half of these having been administered to more than 20 patients each. The most frequently applied radiotracer was the glucose analogue 2-[(18)F]fluoro-2-deoxy- D-glucose (FDG), which was utilised in more than 84% of all PET procedures. For this tracer, the median value for activities applied for examinations in the three-dimensional (3D) acquisition mode was only half of that used for two-dimensional (2D) measurements. Based on a statistical analysis of the distribution of mean FDG activities administered to patients in the 48 PET facilities who responded to our inquiry, diagnostic reference levels of 370 and 200 MBq are proposed for the 2D and the 3D mode, respectively.

Visualization of prostate cancer with 11C-choline positron emission tomography.

Visualization of prostate cancer with positron emission tomography (PET) using 2-[18F]-2-deoxy-D-glucose (FDG) as radiopharmaceutical is limited by the low uptake of FDG in the tumor and by radioactivity excreted into the bladder. More specific PET radiopharmaceuticals would be welcome. Carbon-11 labeled choline (CHOL) is a new radiopharmaceutical potentially useful for tumor imaging as it is incorporated in the cell membranes as phosphatidylcholine. We prospectively studied the visualization of prostate cancer using CHOL PET. A total of 25 consecutive patients with histologically proven prostate cancer and five patients with a benign prostate were included. PET images were performed with an ECAT HR(+) using 400MBq CHOL. Data acquisition was started at 5 minutes post-injection. Attenuation-corrected images were evaluated visually. Standardized uptake values (SUV) were calculated of the normal prostate gland and of the prostate tumor tissue. The normal prostate was visualized with a mean SUV of 2.3 (range 1.3-3.2). The primary tumor could be visualized with a mean SUV of 5.0 (range 2.4-9.5). Lymph node metastases >5mm could be identified. Non-specific uptake of CHOL was noticed in the intestines. Little to no radioactivity in the bladder was observed. Carbon-11-choline is avidly taken up in prostate cancer, both primary tumor and lymph node metastases, in the virtual absence of urinary radioactivity. These results confirm the early results obtained by others and permit further clinical research on the value of CHOL PET as a metabolic imaging technique in areas where conventional imaging have a limited sensitivity.

A shifting landscape: what will be next FDG in PET oncology?

The tumor-seeking agent most widely used in positron emission tomography (PET) is 2-(18)F-fluorodeoxy-D-glucose (FDG). The clinical usefulness of FDG PET has already been proved in detecting, staging and restaging various kinds of malignant tumors, but nuclear medicine physicians suffer from a "diagnostic dilemma," in which a relatively high false positive ratio of FDG PET in diagnosing malignant tumors prevails. To increase more specific tumor uptake or more specific tumor characterization, numerous PET radiopharmaceuticals have been developed, and some of them are being tested in clinical trials. This review will briefly survey the tumor uptake mechanism and clinical significance of representative non-FDG PET radiopharmaceuticals used in clinical trials for patients with cancers.

The role of nuclear medicine in monitoring treatment in skeletal malignancy

The nuclear medicine bone scan has historically been one of the most common investigations to stage and monitor skeletal malignancy. Current guidelines for using radiographs to assess the response of skeletal metastases to systemic therapy are limited in their ability to give a timely result. Despite some minor limitations caused by the flare phenomenon, skeletal scintigraphy remains widely used for this purpose, both clinically and in trials of new cancer treatments. Nuclear medicine has also played an important role in the posttherapy evaluation of primary bone tumors, both with bone agents and nonspecific tumor agents, such as 201Tl. In the future, it is possible that positron emission tomography radiopharmaceuticals such as 18F-fluorodeoxyglucose may prove to be superior in predicting and measuring treatment response in primary and metastatic bone and bone marrow disease, but further work is required in this area.

Regulation of the compounding of positron emission tomography drugs.

Controversial aspects of the regulatory framework for compounding drug products used in positron emission tomography (PET) are discussed. The Food and Drug Administration Modernization Act of 1997 (FDAMA), which amends the Federal Food, Drug, and Cosmetic Act (FFDCA), required that FDA establish approval (new drug application [NDA] and abbreviated new drug application [ANDA]) procedures and current good manufacturing practice (CGMP) requirements for PET drugs; this seems to conflict with differentiation between manufacturing and compounding in FFDCA. Compounding by pharmacists is implied in the FDAMA section on PET, but specific mention of "pharmacist" needs to be included. Congress apparently did not intend for compounded PET drugs to be regulated differently from other drugs. Although FDA has waived NDA and ANDA fees for three PET radiopharmaceuticals, revision of FDAMA to exempt PET drug products from regulations placed on manufacturing is needed. Without relief from the current regulations, many academic PET centers are likely to close; this would violate FDAMA's stated intent of making PET available to patients at reasonable cost. Also problematic is FDAMA's prohibition of compounding "regularly or in inordinate amounts" a product that is commercially available; the common PET radiopharmaceutical fludeoxyglucose F 18 injection, for example, is commercially available. A sensible alternative to NDA or ANDA and CGMP requirements would be the enforcement of USP standards for PET drugs by state boards of pharmacy.

Tracer kinetic modeling in nuclear cardiology

The introduction of tracer kinetic modeling techniques in conjunction with nuclear imaging has allowed the assessment of physiologic processes in the myocardium in a noninvasive and quantitative manner. Alongside the development of novel radiopharmaceuticals for both positron emission tomography and single photon emission computed tomography is the clarification of their pharmacology, pharmacokinetics, and modeling strategies for assessment of physiologic rates from imaging data. Image analysis and tracer kinetic modeling techniques used in nuclear cardiology must address unique considerations related to the heart. The most commonly used tracers and modeling techniques are presently discussed, with particular attention given to methods that allow absolute quantitation of physiologic processes. The applications of these techniques are obvious in research protocols and may find more use in future clinical studies. (J Nucl Cardiol 2000;7:686-700.)

Medical image registration

Problems related to file structures, transfer and networking plays an important role is in medical imaging in the early detection of cancers. Radiologists often have difficulty locating and accurately identifying cancer tissue, even with the aid of structural information such as CT and MRI because of the low contrast between the cancer and the surrounding tissues in CT and MRI images. Using SPECT and radioactively labeled monoclonal antibodies it is possible to obtain high contrast images of the concentration of antibodies in tumors. However, sometimes it is difficult to determine the precise location ofthe high concentration of the radioactive isotope in SPECT or PET images in relation to anatomic structures, such as vital organs and surrounding healthy tissue. Image registration is a visualization tool that can significantlyaid in the early detection oftumors and other diseases, and aid in improving the accuracy of diagnosis. The problems related to multimodality imaging can be separated into three groups; a) problems related to file structures, transfer and networking, b) registration, and c) visualization of the composite images. an image with normal uptake properties to an image with suspected abnormalities. In addition, image registration of SPECT and PET images and the registration of SPECT and PET images with anatomic atlases, provide an important means to evaluate comparative uptake properties of SPECT and PET radiopharmaceuticals, and to correlate uptake properties with anatomy. Medical image registration has been applied to the diagnosis of breast cancer, colon cancer, cardiac studies, wrist and other injuries, inflammatory diseases and different neurological disorders including brain tumors, Alzheimer's disease and schizophrenia. This method has also been utilized in radiotherapy, mostly for brain tumors, and by cranio-facial surgeons to prepare for and simulate complexsurgical procedures. One area where image registration Two basic types of medical images are made: functional body images (such as SPECT or PET scans), which provide physiological information, and structural images (such as CT or MRI), which provide an anatomic map of the body. Different medical imaging techniques may provide scans with complementary and occasionally conflicting information. The combination of images can often lead to additional clinical information not apparent in the separate images. The goal of image fusion is to impose a structural anatomic framework on functional images. Often in a functional image, there simply isn't enough anatomic detail to determine the position ofa tumor or other lesion. Although, the construction of a composite, overlapping medical image described in the field as medical image registration has been primarily used in the fusion offunctional and anatomical images, it has also been applied to a series of the same modality images. Examples of this are registration of SPECT images of the same subject in follow-up studies or in a comparison of Functional imaging using single photon emission computed tomography (SPECT) and positron emission tomography (PET) is extremely valuable in the diagnosis of various disorders. Uncertainty in the anatomic definition on SPECT and PET images, however, sometimes limits their usefulness. To overcome this problem, a combination ofmagnetic resonance images (MRI) and X-ray computed tomography (CT) images with functional SPECT or PET images of the same sections of the body, is used. This provides complementary anatomic (MRI or CT) and physiological (SPECT or PET) information that is of great importance to research, diagnosis, and treatment.

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.

Pharmacokinetics of radiotracers in human plasma during positron emission tomography.

Many radiopharmaceuticals for positron emission tomography (PET) are substantially metabolized in peripheral organs. Pharmacological treatments intended to alter cerebral metabolism might also alter radiotracer metabolism, consequently altering the cerebral uptake. First-order rate constants for the metabolism of PET tracers can be calculated by a linear graphical method from the precursor and metabolite concentrations measured in plasma extracts fractionated by HPLC. We tested the effects of specific pharmacological challenges on the plasma kinetics of six tracers used for PET studies of neurotransmission. The rate of O-methylation of circulating [(18)F]fluorodopa, a tracer of dopa decarboxylase activity in brain, was unaffected by pretreatment with amantadine, an antagonist of glutamate receptors. [(11)C]Deprenyl, a tracer of monoamine oxidase activity, was rapidly metabolized to [(11)C]methamphetamine and polar metabolites in healthy volunteers. The net rate constant of this metabolism was three times higher in a group of subjects under treatment for epilepsy, consistent with induction of hepatic microsomal enzymes by antiepileptic drugs. [(11)C]Sch 23390, a ligand for dopamine D1 receptors, was rapidly metabolized to polar metabolites. The net rate constant of metabolism was unaffected by pretreatment with lorazepam. [(11)C]-(S)-Nicotine, a ligand for nicotinic receptors, was rapidly metabolized to [(11)C]-(S)-cotenine, which is less polar than the parent compound. Pretreatment with mazindol, a dopamine uptake inhibitor, was without effect on peripheral metabolism of [(11)C]-(S)-nicotine. [(11)C]WIN 35,428, a tropane derivative which labels dopamine uptake sites, was metabolized to a nonpolar metabolite, but so slowly that the rate constant of this process could not be calculated. [(11)C]Raclopride, a ligand for dopamine D2 receptors, was first metabolized to a nonpolar metabolite, which then yielded two hydrophilic metabolites. The initial metabolic step was substantially blocked by pretreatment with amphetamine, possibly indicative of competitive inhibition of microsomal oxidation. Together, these results indicate that the linear graphic method is useful for estimating the kinetics of the plasma metabolism of many widely used PET tracers. Drug-drug interactions were revealed in subjects treated with specific pharmacological agents prior to tracer administration.

Pharmacokinetics of radiotracers in human plasma during positron emission tomography

Many radiopharmaceuticals for positron emission tomography (PET) are substantially metabolized in peripheral organs. Pharmacological treatments intended to alter cerebral metabolism might also alter radiotracer metabolism, consequently altering the cerebral uptake. First-order rate constants for the metabolism of PET tracers can be calculated by a linear graphical method from the precursor and metabolite concentrations measured in plasma extracts fractionated by HPLC. We tested the effects of specific pharmacological challenges on the plasma kinetics of six tracers used for PET studies of neurotransmission. The rate of O-methylation of circulating [18F]fluorodopa, a tracer of dopa decarboxylase activity in brain, was unaffected by pretreatment with amantadine, an antagonist of glutamate receptors. [11C]Deprenyl, a tracer of monoamine oxidase activity, was rapidly metabolized to [11C]methamphetamine and polar metabolites in healthy volunteers. The net rate constant of this metabolism was three times higher in a group of subjects under treatment for epilepsy, consistent with induction of hepatic microsomal enzymes by antiepileptic drugs. [11C]Sch 23390, a ligand for dopamine D1 receptors, was rapidly metabolized to polar metabolites. The net rate constant of metabolism was unaffected by pretreatment with lorazepam. [11C]-(S)-Nicotine, a ligand for nicotinic receptors, was rapidly metabolized to [11C]-(S)-cotenine, which is less polar than the parent compound. Pretreatment with mazindol, a dopamine uptake inhibitor, was without effect on peripheral metabolism of [11C]-(S)-nicotine. [11C]WIN 35,428, a tropane derivative which labels dopamine uptake sites, was metabolized to a nonpolar metabolite, but so slowly that the rate constant of this process could not be calculated. [11C]Raclopride, a ligand for dopamine D2 receptors, was first metabolized to a nonpolar metabolite, which then yielded two hydrophilic metabolites. The initial metabolic step was substantially blocked by pretreatment with amphetamine, possibly indicative of competitive inhibition of microsomal oxidation. Together, these results indicate that the linear graphic method is useful for estimating the kinetics of the plasma metabolism of many widely used PET tracers. Drug–drug interactions were revealed in subjects treated with specific pharmacological agents prior to tracer administration. Synapse 34:124–134, 1999. © 1999 Wiley-Liss, Inc.

The Role of the Practice of Nuclear Pharmacy in Positron Emission Tomography

As nuclear medicine evolved from an obscure research tool to a mainstream clinical diagnostic and therapeutic modality, so has the role of the practice of pharmacy in nuclear medicine also evolved. A similar evolution is unfolding today in the practice of positron emission tomography (PET). The skills of many diverse professionals, including pharmacists, are essential for the safe and efficient operation of a modern PET facility. The importance of the role of pharmacists in PET has been increasing as the use of PET radiopharmaceuticals has matured from research to clinical to commercial arenas. While it is clear that pharmacists can contribute clinical and technical skills to the operation of a PET center, perhaps one of the most important factors influencing the increased role of pharmacists in PET is their expertise and experience in the drug regulatory process. The commercial distribution of PET radiopharmaceuticals, primarily [ 18F]2-fluorodeoxyglucose (FDG), is currently being performed by a variety of corporate and institutional facility partnerships, with the likelihood of several new players entering the marketplace in the near future. This factor has served to dramatically increase the role for nuclear pharmacy in PET. The practice of nuclear pharmacy is a well-established component of PET. The role of nuclear pharmacists in PET is complementary to the many other professionals currently practicing in this specialty. With the rapidly increasing clinical demand for FDG imaging, it is likely that the number of facilities and institutions entering into the commercial distribution of PET radiopharmaceuticals will also increase. Such growth will also serve to solidify and expand the role for the practice of nuclear pharmacy in PET.

Design of hypoxia-targeting radiopharmaceuticals: selective uptake of copper-64 complexes in hypoxic cells in vitro.

The well-known perfusion tracer CuPTSM, labelled with 62Cu or 64Cu, is believed to be trapped in cells non-selectively by a bioreductive mechanism. It is proposed that by modifying the ligand to increase its electron donor strength (for example by adding alkyl functionality or replacing sulphur ligands with oxygen ligands), the copper complexes will become less easily reduced and tracers with selectivity for hypoxic tissues could thus be developed. The aim of this work was to prepare 64Cu-labelled complexes of two series of ligands, based on the bis(thiosemicarbazone) (13 ligands) and bis(salicylaldimine) (3 ligands) skeletons, and to evaluate the hypoxia dependence of their uptake in cells. The complexes were incubated with Chinese hamster ovary cells under normoxic and hypoxic conditions, and the cells isolated by centrifugation to determine radioactivity uptake at various time points up to 90 min. Several members of both series demonstrated significant (P<0.05) or highly significant (P<0.01) hypoxia selectivity, indicating that both series of complexes offer a basis for development of hypoxia-targeting radiopharmaceuticals for positron emission tomography (60Cu, 61Cu, 62Cu, 64Cu) and targeted radiotherapy (64Cu, 67Cu).

PET radiopharmaceuticals: state-of-the-art and future prospects

In this review we provide a conceptual overview of radiopharmaceuticals containing positron-emitting isotopes, not a catalog of radiopharmaceuticals or details of syntheses. We hope to provide an integrated framework for understanding the radiopharmaceuticals that are available at this time, describing both their strengths and weaknesses, and to look forward to some of the improvements that might be anticipated in the next decade. The range of biology that can be studied with positron emission tomography (PET) radiopharmaceuticals has greatly expanded, involving more sophisticated tracers and more sophisticated data analysis. PET measurements now encompass increasingly more specific aspects of human biochemistry and physiology as described in this review. As the biology being studied becomes more complex, the demands on the radiopharmaceutical and the methods of data analysis also become more complex. New synthetic chemistry and data analysis must develop in tandem. Radiopharmaceuticals must be designed to ensure that the rate determining step that is of interest is the one reflected in the data from the radiopharmaceutical. The challenge to the PET community of chemists, biologists, and physicians is to apply new knowledge of human biochemistry for developing and validating useful PET radiopharmaceuticals that will, in turn, produce useful nuclear medicine procedures. Initially the synthesis of a compound containing a short-lived radionuclide was a triumph in itself. However as the science advances the radiochemical synthesis becomes just the first step in a long trail that terminates in the compound being used to provide data on biological processes via a well-designed PET experiment. The resulting list of compounds and experiments should be as diverse as all of human biology and pathophysiology.

Positron emission tomography (PET) scanning in breast cancer.

primary diagnosis, more accurate non-invasive Quantitative analysis techniques include dynamic staging, and more effective methods of following studies which generate absolute glucose metabolic therapy and establishing prognosis. A large number rates and simple relative quantitative ratios, known of new or improved imaging techniques have been as standardized uptake values or SUVs [3, 6]. developed in recent years yet most patients still Simple qualitative visual analysis of the images has require multiple examinations of various organs, also shown high accuracy [6, 7]. including ultrasound of the liver, isotope bone Several studies have examined the initial detecscans, mammograms and CT scans. Furthermore, tion and staging of breast cancer using FDG–PET the current sensitivities and/or specificities of these scans. Wahl and colleagues detected 10 out of 10 methods leave much room for improvement. primary breast lesions and, although these were Positron emission tomography (PET) imaging has generally large lesions (3.2–12 cm), 2 of the patients recently shown promise as a single technique that had dense glandular breast tissue with negative might have equivalent or better accuracy than the mammograms [4]. In a series of 28 patients with other current methods combined [1–4]. 35 suspect breast masses, 27 of which were found The greatest developments in PET imaging to be malignant, Adler et al reported a sensitivity during the 1990s have been in oncology. A number of 90% and specificity of 100% with primary of PET radiopharmaceuticals have been utilized lesions as small as 0.9 cm being correctly identified for oncological investigations including labelled as tumour [8]. In their quantitative analysis, the hormones or their analogues, labelled amino acids, malignant lesions had a mean FDG uptake value labelled hypoxia agents and labelled thymidine [2, (SUV) of 12.8, while benign solid lesions averaged 3]. However, the vast majority of the work to date 1.8 and benign cysts 0.2. Furthermore, there was a has centred on the use of fluorodeoxyglucose labsignificant correlation between normalized FDG elled with Fluorine-18 (18FDG). The 2 h half life uptake and the histological nuclear grade of the not only makes whole body imaging practical but primary lesion. Tse et al from the University of allows for multicentre distribution of tracer. The California at Los Angeles also reported 100% high aerobic glycolytic rate of most tumours means specificity but a false negative rate of 16% [9]. that there is a much higher uptake of FDG in One of their false negative studies had diffuse malignant tissues than in normal tissue. These high microscopic foci and the other had a low grade glycolytic rates are most likely the result of tumour with microscopic foci of invasion. Lesions increased glucose transporter expression and less than 1 cm were detected. While mammography increased hexokinase activity in tumours [2, 3, 5]. was less specific, it was complementary in detecting Moderate levels of hypoxia also increase tumour a FDG–PET negative non-palpable lesion. The glucose uptake rates by 30% or more [5]. Most following year, Nieweg et al from the MD modern PET scanners have large fields of view, Anderson Cancer Center reported a series of 20