Positron Emission Tomography Radiochemistry Research Articles

Significance of Cartridges and Resins used in a Purification Column during 18F-fluorodeoxyglucose Synthesis.

The aims and objective of this study to share the 15 years of working experience regarding importance of cartridges and resins used in a Purification Column during 18F-FDG synthesis. 18F- flourodeoxyglucose (18F-FDG) is common radiotracer used in positron emission tomography (PET). 18F-FDG is synthesized in a PET radiochemistry synthesis module and purification column is an integral part of 18F-FDG synthesis. The purification column has four integral parts, namely of ion exchange retardation resin, cation exchange resin, C18 bonded silica, Neutral Alumina. The purification column plays a very important role during the synthesis of 18F-FDG. If all parts of the purification column are intact, then maximum transfer of produced 18F-FDG from reaction vessels to the final product vial takes place. The total yield of 18F-FDG is also dependent upon the purification column. If all components of purification column placed tightly and properly charged then there is a high possibility of maximum yield of final product without impurities.

Synthesis of 68Ga-radiopharmaceuticals using both generator-derived and cyclotron-produced 68Ga as exemplified by [68Ga]Ga-PSMA-11 for prostate cancer PET imaging.

[68Ga]Ga-PSMA-11, a urea-based peptidomimetic, is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that targets the prostate-specific membrane antigen (PSMA). The recent Food and Drug Administration approval of [68Ga]Ga-PSMA-11 for PET imaging of patients with prostate cancer, expected follow-up approval of companion radiotherapeutics (e.g., [177Lu]Lu-PSMA-617, [225Ac]Ac-PSMA-617) and large prostate cancer patient volumes requiring access are poised to create an unprecedented demand for [68Ga]Ga-PSMA-11 in nuclear medicine clinics around the world. Meeting this global demand is going to require a variety of synthesis methods compatible with 68Ga eluted from a generator or produced on a cyclotron. To address this urgent need in the PET radiochemistry community, herein we report detailed protocols for the synthesis of [68Ga]Ga-PSMA-11, (also known as HBED-CC, Glu-urea-Lys(Ahx)-HBED-CC and PSMA-HBED-CC) using both generator-eluted and cyclotron-produced 68Ga and contrast the pros and cons of each method. The radiosyntheses are automated and have been validated for human use at two sites (University of Michigan (UM), United States; Royal Prince Alfred Hospital (RPA), Australia) and used to produce [68Ga]Ga-PSMA-11 for patient use in good activity yields (single generator, 0.52 GBq (14 mCi); dual generators, 1.04-1.57 GBq (28-42 mCi); cyclotron method (single target), 1.47-1.89 GBq (40-51 mCi); cyclotron method (dual target), 3.63 GBq (98 mCi)) and high radiochemical purity (99%) (UM, n = 645; RPA, n > 600). Both methods are appropriate for clinical production but, in the long term, the method employing cyclotron-produced 68Ga is the most promising for meeting high patient volumes. Quality control testing (visual inspection, pH, radiochemical purity and identity, radionuclidic purity and identity, sterile filter integrity, bacterial endotoxin content, sterility, stability) confirmed doses are suitable for clinical use, and there is no difference in clinical prostate cancer PET imaging using [68Ga]Ga-PSMA-11 prepared using the two production methods.

A practical guide to automating fluorine-18 PET radiochemistry using commercially available cassette-based platforms

This Tutorial Account aims to be a useful educational resource which describes how to automate fluorine-18 positron emission tomography (PET) radiochemistry using cassette-based automated radiosynthesis platforms.

Synthesis of high-molar-activity [18F]6-fluoro-L-DOPA suitable for human use via Cu-mediated fluorination of a BPin precursor.

[18F]6-fluoro-L-DOPA ([18F]FDOPA) is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that is used to image Parkinson's disease, brain tumors, and focal hyperinsulinism of infancy. Despite these important applications, [18F]FDOPA PET remains underutilized because of synthetic challenges associated with accessing the radiotracer for clinical use; these stem from the need to radiofluorinate a highly electron-rich catechol ring in the presence of an amino acid. To address this longstanding challenge in the PET radiochemistry community, we have developed a one-pot, two-step synthesis of high-molar-activity [18F]FDOPA by Cu-mediated fluorination of a pinacol boronate (BPin) precursor. The method is fully automated, has been validated to work well at two separate sites (an academic facility with a cyclotron on site and an industry lab purchasing [18F]fluoride from an outside vendor), and provides [18F]FDOPA in reasonable radiochemical yield (2.44 ± 0.70 GBq, 66 ± 19 mCi, 5 ± 1%), excellent radiochemical purity (>98%) and high molar activity (76 ± 30 TBq/mmol, 2,050 ± 804 Ci/mmol), n = 26. Herein we report a detailed protocol for the synthesis of [18F]FDOPA that has been successfully implemented at two sites and validated for production of the radiotracer for human use.

Antibody Fragment and Affibody ImmunoPET Imaging Agents: Radiolabelling Strategies and Applications.

Antibodies have long been recognised as potent vectors for carrying diagnostic medical radionuclides, contrast agents and optical probes to diseased tissue for imaging. The area of ImmunoPET combines the use of positron emission tomography (PET) imaging with antibodies to improve the diagnosis, staging and monitoring of diseases. Recent developments in antibody engineering and PET radiochemistry have led to a new wave of experimental ImmunoPET imaging agents that are based on a range of antibody fragments and affibodies. In contrast to full antibodies, engineered affibody proteins and antibody fragments such as minibodies, diabodies, single‐chain variable region fragments (scFvs), and nanobodies are much smaller but retain the essential specificities and affinities of full antibodies in addition to more desirable pharmacokinetics for imaging. Herein, recent key developments in the PET radiolabelling strategies of antibody fragments and related affibody molecules are highlighted, along with the main PET imaging applications of overexpressed antigen‐associated tumours and immune cells.

Production of diverse PET probes with limited resources: 24 18F-labeled compounds prepared with a single radiosynthesizer

New radiolabeled probes for positron-emission tomography (PET) are providing an ever-increasing ability to answer diverse research and clinical questions and to facilitate the discovery, development, and clinical use of drugs in patient care. Despite the high equipment and facility costs to produce PET probes, many radiopharmacies and radiochemistry laboratories use a dedicated radiosynthesizer to produce each probe, even if the equipment is idle much of the time, to avoid the challenges of reconfiguring the system fluidics to switch from one probe to another. To meet growing demand, more cost-efficient approaches are being developed, such as radiosynthesizers based on disposable "cassettes," that do not require reconfiguration to switch among probes. However, most cassette-based systems make sacrifices in synthesis complexity or tolerated reaction conditions, and some do not support custom programming, thereby limiting their generality. In contrast, the design of the ELIXYS FLEX/CHEM cassette-based synthesizer supports higher temperatures and pressures than other systems while also facilitating flexible synthesis development. In this paper, the syntheses of 24 known PET probes are adapted to this system to explore the possibility of using a single radiosynthesizer and hot cell for production of a diverse array of compounds with wide-ranging synthesis requirements, alongside synthesis development efforts. Most probes were produced with yields and synthesis times comparable to literature reports, and because hardware modification was unnecessary, it was convenient to frequently switch among probes based on demand. Although our facility supplies probes for preclinical imaging, the same workflow would be applicable in a clinical setting.

A novel radiochemical approach to 1-(2'-deoxy-2'-[(18) F]fluoro-β-d-arabinofuranosyl)cytosine ((18) F-FAC).

(18) F-FAC (1-(2'-deoxy-2'-[(18) F]fluoro-β-D-arabinofuranosyl)-cytosine) is an important 2'-fluoro-nucleoside-based positron emission tomography (PET) tracer that has been used for in vivo prediction of response to the widely used cancer chemotherapy drug gemcitabine. Previously reported synthetic routes to (18) F-FAC have relied on early introduction of the (18) F radiolabel prior to attachment to protected cytosine base. Considering the (18) F radiochemical half-life (110 min) and the technical challenges of multi-step syntheses on PET radiochemistry modular systems, late-stage radiofluorination is preferred for reproducible and reliable radiosynthesis with in vivo applications. Herein, we report the first late-stage radiosynthesis of (18) F-FAC. Cytidine derivatives with leaving groups at the 2'-position are particularly prone to undergo anhydro side-product formation upon heating because of their electron density at the 2-carbonyl pyrimidone oxygen. Our rationally developed fluorination precursor showed an improved reactivity-to-stability ratio at elevated temperatures. (18) F-FAC was obtained in radiochemical yields of 4.3-5.5% (n = 8, decay-corrected from end of bombardment), with purities ≥98% and specific activities ≥63 GBq/µmol. The synthesis time was 168 min.

Radiopharmaceutical Chemistry with Iodine-124: A Non-Standard Radiohalogen for Positron Emission Tomography

Positron emission tomography (PET) is a powerful molecular imaging technology with the ability to image and monitor molecular events in vivo and in real time. With the increased application of PET radiopharmaceuticals for imaging physiological and pathological processes in vivo, there is a demand for versatile positron emitters with longer physical and biological half-lives. Traditional PET radionuclides, such as carbon-11 ((11)C) and fluorine-18 ((18)F), have relatively short half-lives (20 min and 110 min, respectively). Among the currently available positron emitters, the non-standard radiohalogen iodine-124 ((124)I) has the longest physical half-life at 4.2 d. This, combined with the well characterized radiochemistry of radioiodine, is contributing to the increasing utility of (124)I in investigating slow and complex pharmacokinetic processes in clinical nuclear medicine and small animal PET imaging studies. This review will summarize the progress to date on the potential of (124)I as a positron emitting nuclide for molecular imaging purposes, beginning with the production of (124)I. Particular emphasis will be placed on the basic radiochemistry as it applies to the production of various (124)I-labeled compounds, from small molecules, to biomolecules such as peptides and proteins, and finally to macromolecules like nanoparticles. The review will conclude by highlighting promising future directions in using (124)I as a positron emitter in PET radiochemistry and molecular imaging.

Microwave-assisted radiosynthesis of [18F]fluorinated fatty acid analogs

Microwave reactors remain largely underutilized in the field of positron emission tomography (PET) chemistry. This is particularly unfortunate since microwave synthesis elegantly addresses two of the most critical issues of PET radiochemistry with short-lived radionuclides: reaction rate and side-product formation. In this study, we investigate the efficiency of synthesis of terminally [(18)F]fluorinated fatty acid analogs using a commercial microwave reactor in comparison with conventional heating (CH). The labeling precursors were methyl esters of terminally substituted alkyl bromides and iodides. Duration and temperatures of the [(18)F]fluorination reaction were varied. Chemical and radiochemical purities, and radiochemical yields were investigated for conventional (CH) and microwave-assisted (MW) radiosyntheses. The results demonstrate that microwave heating enhanced [(18)F]fluoride incorporation to >95% (up to 55% improvement), while reducing reaction times to 2 min (∼ 10-fold reduction) or temperatures to 55-60 °C (20 °C reduction). Overall decay-corrected radiochemical yields of purified [(18)F]fluoro fatty acids were higher (MW = 49.0 ± 4.5%, CH = 23.6 ± 3.5%, P < .05) with microwave heating and side-products were notably fewer. For routine synthesis of [(18)F]fluoro fatty acid analogs, microwave heating is faster, milder, cleaner, less variable and higher yielding than CH and therefore the preferred reaction method.

IC-PL2: Amyloid imaging: Developments, challenges, future direction

The first in vivo positron emission tomography (PET) imaging studies of amyloid-beta (Aβ) in human subjects were reported by the UCLA group in 2002 using a fluorine-18 labeled membrane dye derivative, [F-18]FDDNP, that bound preferentially to both Aβ plaques and neurofibrillary tangles (NFT) in the brains of Alzheimer's disease (AD) patients relative to elderly control subjects. Groups from Pittsburgh and Toronto followed in 2004 with literature reports of PET imaging studies in AD and control subjects using Aβ-selective carbon-11 labeled thioflavin-T ([C-11]PIB) and stilbene ([C-11]SB-11) derivatives, respectively. Researchers have sought to employ these PET agents in cross-sectional and longitudinal studies of Aβ deposition in a variety of non-invasive imaging studies in amyloid-based diseases. In addition, investigators have sought to expand the choice of Aβ-specific radioligands to include other F-18 and C-11 labeled compounds for PET imaging applications, as well as I-123 labeled agents for single photon emission computed tomography (SPECT) imaging studies. Over the past 4 years, literature reports of Aβ imaging in human subjects using PET have exploded, with more than 70 publications in a variety of subject populations. The vast majority of these studies have utilized [C-11]PIB, but the relatively short half-life of carbon-11 (20 min) has limited its distribution to about 40 specialized PET radiochemistry facilities throughout the world. The development of a more convenient, longer-lived (110 min) F-18 labeled radioligand with in vivo properties comparable to those of [C-11]PIB has been an active area of research over the past several years with some recent encouraging results. In contrast, efforts to develop a SPECT Aβ imaging agent have been largely unsuccessful. PET Aβ imaging studies have provided some important insights into the pathophysiology of amyloid deposition, particularly in mild cognitive impairment (MCI), healthy elderly controls, and familial AD subjects. Aβ PET methodology is proving valuable in helping to assess the amyloid cascade hypothesis, as a diagnostic agent for brain amyloid deposition, and as a potential surrogate marker of therapeutic efficacy in anti-Aβ drug trials.

Small animal positron emission tomography in food sciences

Positron emission tomography (PET) is a 3-dimensional imaging technique that has undergone tremendous developments during the last decade. Non-invasive tracing of molecular pathways in vivo is the key capability of PET. It has become an important tool in the diagnosis of human diseases as well as in biomedical and pharmaceutical research. In contrast to other imaging modalities, radiotracer concentrations can be determined quantitatively. By application of appropriate tracer kinetic models, the rate constants of numerous different biological processes can be determined. Rapid progress in PET radiochemistry has significantly increased the number of biologically important molecules labelled with PET nuclides to target a broader range of physiologic, metabolic, and molecular pathways. Progress in PET physics and technology strongly contributed to better scanners and image processing. In this context, dedicated high resolution scanners for dynamic PET studies in small laboratory animals are now available. These developments represent the driving force for the expansion of PET methodology into new areas of life sciences including food sciences. Small animal PET has a high potential to depict physiologic processes like absorption, distribution, metabolism, elimination and interactions of biologically significant substances, including nutrients, 'nutriceuticals', functional food ingredients, and foodborne toxicants. Based on present data, potential applications of small animal PET in food sciences are discussed.

Synthesis and biodistribution of an 18F-labelled resveratrol derivative for small animal positron emission tomography

Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a naturally occurring phytoalexin and polyphenol existing in grapes and various other plants, and one of the best known 'nutriceuticals'. It shows a multiplicity of beneficial biological effects, particularly, by attenuating atherogenic, inflammatory, and carcinogenic processes. However, despite convincing evidence from experimental and clinical studies, data concerning the role of resveratrol and other members of the large polyphenols family for human health is still a matter of debate. One reason for this is the lack of suitable sensitive and specific methods, which would allow direct assessment of biodistribution, biokinetics, and the metabolic fate of these compounds in vivo. The unique features of positron emission tomography (PET) as a non-invasive in vivo imaging methodology in combination with suitable PET radiotracers have great promise to assess quantitative information on physiological effects of polyphenols in vivo. Herein we describe the radiosynthesis of an (18)F-labelled resveratrol derivative, 3,5-dihydroxy-4'-[(18)F]fluoro-trans-stilbene ([(18)F]-1), using the Horner-Wadsworth-Emmons reaction as a novel radiolabelling technique in PET radiochemistry for subsequent functional imaging of polyphenol metabolism in vivo. In a typical "three-step/one-pot" reaction, (18)F-labelled resveratrol derivative [(18)F]-1 could be synthesized within 120-130 min including HPLC separation at a specific radioactivity of about 90 GBq/mumol. The radiochemical yield was about 9% (decay-corrected) related to [(18)F]fluoride and the radiochemical purity exceeded 97%. First radiopharmacological evaluation included measurement of biodistribution ex vivo and positron emission tomography (PET) studies in vivo after intravenous application of [(18)F]-1 in male Wistar rats using a dedicated small animal PET camera with very high spatial resolution. Concordantly with data on bioavailability and metabolism of native resveratrol from the literature, these investigations revealed an extensive uptake and metabolism in the liver and kidney, respectively, of [(18)F]-1. This study represents the first investigation of polyphenols in vivo by means of PET.

PET Tracers and Radiochemistry

This paper provides a brief review of the radiochemistry of radiopharmaceuticals used in positron emission tomography (PET). It includes some history of PET, the basic formation of radionuclides in a cyclotron target, the processing of the precursor molecules into a useful PET radiotracer and the clinical significance and outlook for PET radiotracers. This review is based on a series of recent books and articles outlining the fundamental goals of PET and how radiochemistry plays a part in achieving these goals. It is also drawn from the literature that has been developed in PET over the last 30 years since PET became a research and valuable clinical tool. PET is a growing field and the clinical applications of the chemistry and technology have just begun to be explored. There is a great deal left to do in order to explore the full potential of PET in the clinic.

The Planning and Design of a New PET Radiochemistry Facility

The objectives of the Mayo positron emission tomography (PET) radiochemistry facility are the production of PET drugs for clinical service of our in-house patients, commercial distribution of PET drug products, and development of new PET drugs. The factors foremost in the planning and design phases were the current regulatory climate for PET drug production, radiation safety issues, and effective production flow. A medium-energy cyclotron was preferred for its small footprint to allow a compact vault, its high-proton energy to offer a higher product radioactivity; and its research capabilities. A vault installation was chosen instead of a self-shielded machine for improved access and ease of maintenance. Adjacent to the cyclotron is an area that houses the support equipment and a large dedicated workshop to support machine maintenance and targetry development. The total floor area of the PET radiochemistry facility is 344.2 m 2 (3,705.5 ft 2), of which the radiochemistry laboratory occupies 130.7 m 2 (1,407 ft 2). To reduce environmental contamination of PET drug products, the laboratory contains a controlled-air environment class 10,000 (M5.5) clean room with access via an interlocking entry change area. A fully shielded isolator (class 100 [M3.5]) is located in the clean room. The PET drugs are delivered via shielded tubing between the synthesizer and isolator. Inside the isolator, there is an automated device for dispensing the PET drug into either a bulk-activity vial or a unit-dose syringe. The dispensed PET radiopharmaceutical then passes through a hatch to a dedicated area where it is packaged for in-house use or commercial distribution. Unit doses for in-house patients are transported via pneumatic tube to the PET imaging area 76.2 m (250 ft) away. There is extensive radiation area monitoring throughout the facility that continuously measures radiation levels. We believe that our new PET radiochemistry facility not only meets overall objectives, but also provides an ergonomic, efficient working environment for the production and development of PET drugs. (Mol Imag Biol 2002;4:119–127)

Estudios de neurofarmacología y receptores en la edad avanzada

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.

Neuropharmacology and receptor studies in the elderly.

Functional brain imaging has provided unique and exciting opportunities to strengthen our knowledge of the biologic substrate of the aging brain and neuropsychiatric disorders. Positron emission tomography (PET) is a particularly powerful tool for quantifying the neurobiologic correlates of cognition, mood, and behavior. Initial PET studies of aging, psychiatric disorders, and neurodegenerative disease focused primarily on generalized physiologic parameters such as cerebral blood flow and metabolism, and early neuroreceptor imaging studies relied on relatively nonselective 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 facilitated PET image analysis, radiochemistry techniques, instrumentation, and image processing have helped pave the way for increased emphasis on functional imaging studies of neuropsychiatric disorders. The capability to correct PET image data for the confounding effect of cerebral atrophy permits relationships among age-related brain changes and neurobiologic disease mechanisms to be more accurately examined in the elderly.

The Status of Pet Radiochemistry for Drug Development and Evaluation

Positron emission tomography (PET), when coupled to appropriate organic radiotracers, is a powerful quantitative imaging technique for probing biochemical pathways, molecular interactions, pharmacokinetics, and pharmacodynamics in humans, including those of developmental drugs. The range of parameters that may be investigated is determined by the availability of effective radiotracers. Developmental drugs may be labeled with positron-emitters to obtain direct information on biodistribution, pharmacokinetics, or metabolism. Alternatively, reference radiotracers for blood flow, metabolism, and receptor or enzyme distribution may be used to assess drug pharmacodynamics and binding site interactions. Each radiotracer must be labeled appropriately with a positron-emitter. Consequently, radiochemical science is a key area for expanding the power of PET for clinical, biochemical, and pharmacological investigations. The most useful positron-emitters, namely carbon-11 and fluorine-18, have short half-lives measured in minutes. Hence, the need to label organic molecules rapidly, efficiently, and regularly for human administration, often at a very high specific radioactivity, is a very special challenge. Here the status of PET radiochemistry is described with special emphasis on recent advances and the potential for application in drug development and evaluation.