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The application of [18F]-fluorodeoxyglucose ([18F]FDG) as a radiotracer to detect sites of inflammation (either due to bacterial infection or primary inflammation) has led to exploring the role of PET in visualizing bacteria directly at sites of infection. However, the results from such efforts are controversial and inconclusive so far. We aimed to assess the limitations of PET as an effective modality in the diagnosis of bacterial infections. Inflammation due to bacterial infections can be visualized by using [18F]FDG-PET. However, the non-specificity of [18F]FDG makes it undesirable to visualize bacteria as the underlying cause of inflammation. Hence, more specific radiotracers that possibly bind to or accumulate in bacteria-specific receptors or enzymes are being explored. Several radiotracers, including 2-deoxy-2-[18F]fluorosorbitol ([18F]FDS), 6-[18F]-fluoromaltose, [11C]para-aminobenzoic acid ([11C]PABA), radiolabeled trimethoprim (11C-TMP) and its analog fluoropropyl-trimethoprim (18F-FPTMP), other radiolabeled sugars, and antimicrobial drugs have been used to image microorganisms. Unfortunately, no progress has been made in translating the results to routine human use; feasibility and other factors have constrained their success in clinical settings. In the current article, we discuss the limitations of direct bacterial visualization with PET tracers, but emphasize the important role of [18F]FDG-PET as the only option for detecting evidence of infection. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most common malignancies in women, with high morbidity and mortality rates. In breast cancer, the use of novel radiopharmaceuticals in nuclear medicine can improve the accuracy of diagnosis and staging, refine surveillance strategies and accuracy in choosing personalized treatment approaches, including radioligand therapy. Nuclear medicine thus shows great promise for improving the quality of life of breast cancer patients by allowing non-invasive assessment of the diverse and complex biological processes underlying the development of breast cancer and its evolution under therapy. This review aims to describe molecular probes currently in clinical use as well as those under investigation holding great promise for personalized medicine and precision oncology in breast cancer.

Many neurodegenerative diseases are neuropathologically characterized by neuronal loss, gliosis, and the deposition of misfolded proteins such as β-amyloid (Aβ) plaques and tau tangles in Alzheimer's disease (AD). In postmortem AD brains, reactive astrocytes and activated microglia are observed surrounding Aβ plaques and tau tangles. These activated glial cells secrete pro-inflammatory cytokines and reactive oxygen species, which may contribute to neurodegeneration. Therefore, in vivo imaging of glial response by positron emission tomography (PET) combined with Aβ and tau PET would provide new insights to better understand the disease process, as well as aid in the differential diagnosis, and monitoring glial response disease-specific therapeutics. There are two promising targets proposed for imaging reactive astrogliosis: monoamine oxidase-B (MAO-B) and imidazoline2 binding site (I2BS), which are predominantly expressed in the mitochondrial membranes of astrocytes and are upregulated in various neurodegenerative conditions. PET tracers targeting these two MAO-B and I2BS have been evaluated in humans. [18F]THK-5351, which was originally designed to target tau aggregates in AD, showed high affinity for MAO-B and clearly visualized reactive astrocytes in progressive supranuclear palsy (PSP). However, the lack of selectivity of [18F]THK-5351 binding to both MAO-B and tau, severely limits its clinical utility as a biomarker. Recently, [18F]SMBT-1 was developed as a selective and reversible MAO-B PET tracer via compound optimization of [18F]THK-5351. In this review, we summarize the strategy underlying molecular imaging of reactive astrogliosis and clinical studies using MAO-B and I2BS PET tracers. [ABSTRACT FROM AUTHOR]

In oncology, biomarker research aimed to provide insights on cancer biology via positron emission tomography (PET) and single photon emission tomography (SPECT) imaging has seen an incredible growth in the past two decades. Despite the increased number of publications on PET/SPECT radiopharmaceuticals, the field lacked standardization of in vitro and in vivo parameters necessary for the characterization of any radiotracer. Through the efforts of the World Molecular Imaging Society Education Committee, this white paper lays down validation studies that are essential to chemically and biologically characterize new radiopharmaceuticals derived from small molecules, peptides or proteins. Finally, a brief overview of the steps toward translation is also presented. Herein, we discuss the following: Chemistry and radiochemistry metrics to establish the identity of the imaging agent. In vitro and in vivo studies to examine the radiotracer's mechanism of action, which includes target specificity, pharmacokinetics and in vivo metabolism. [ABSTRACT FROM AUTHOR]

Evolving scientific evidence has begun to point towards hyperphosphorylated tau as a major neurotoxic component in the pathophysiological development of many major neurodegenerative conditions. In response to a need for accurate and reliable diagnosis and disease monitoring in clinical and trial settings, there has been great effort put into the development of tau radiotracers. While first-generation and second-generation radiotracers have provided a basis for assessing tau, concerns of inadequate specificity and selectivity have continued to motivate further study of these radiotracers and the development of novel radiopharmaceuticals. Given the prospective scientific and clinical value of a valid tau radiotracer, the molecular neuroimaging community must be aware of the most recent developments in the realm of tau radiotracer development. This brief review article will critically overview the most established tau radiotracers and, most importantly, concentrate on the progress of more recently developed tau radiotracers. [ABSTRACT FROM AUTHOR]

Many neurodegenerative diseases are neuropathologically characterized by neuronal loss, gliosis, and the deposition of misfolded proteins such as β-amyloid (Aβ) plaques and tau tangles in Alzheimer’s disease (AD). In postmortem AD brains, reactive astrocytes and activated microglia are observed surrounding Aβ plaques and tau tangles. These activated glial cells secrete pro-inflammatory cytokines and reactive oxygen species, which may contribute to neurodegeneration. Therefore, in vivo imaging of glial response by positron emission tomography (PET) combined with Aβ and tau PET would provide new insights to better understand the disease process, as well as aid in the differential diagnosis, and monitoring glial response disease-specific therapeutics. There are two promising targets proposed for imaging reactive astrogliosis: monoamine oxidase-B (MAO-B) and imidazoline2 binding site (I2BS), which are predominantly expressed in the mitochondrial membranes of astrocytes and are upregulated in various neurodegenerative conditions. PET tracers targeting these two MAO-B and I2BS have been evaluated in humans. [18F]THK-5351, which was originally designed to target tau aggregates in AD, showed high affinity for MAO-B and clearly visualized reactive astrocytes in progressive supranuclear palsy (PSP). However, the lack of selectivity of [18F]THK-5351 binding to both MAO-B and tau, severely limits its clinical utility as a biomarker. Recently, [18F]SMBT-1 was developed as a selective and reversible MAO-B PET tracer via compound optimization of [18F]THK-5351. In this review, we summarize the strategy underlying molecular imaging of reactive astrogliosis and clinical studies using MAO-B and I2BS PET tracers.

The two neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-[Formula: see text] plaques and neurofibrillary tangles of tau protein. Fifteen years ago, Positron Emission Tomography (PET) with Pittsburgh Compound B (11C-PiB) enabled selective in-vivo visualization of amyloid-[Formula: see text] plaque deposits and has since provided valuable information about the role of amyloid-[Formula: see text] deposition in AD. The progression of tau deposition has been shown to be highly associated with neuronal loss, neurodegeneration, and cognitive decline. Until recently it was not possible to visualize tau deposition in-vivo, but several tau PET tracers are now available in different stages of clinical development. To date, no tau tracer has been approved by the Food and Drug Administration for use in the evaluation of AD or other tauopathies, despite very active research efforts. In this paper we review the recent developments in tau PET imaging with a focus on in-vivo findings in AD and discuss the challenges associated with tau tracer development, the status of development and validation of different tau tracers, and the clinical information these provide. [ABSTRACT FROM AUTHOR]

Introduction The production of 18 F-radiotracers using continuous flow microfluidics is under-utilized due to perceived equipment limitations. We describe the dose-on-demand principle, whereby the back-to-back production of multiple, diverse 18 F-radiotracers can be prepared on the same day, on the same microfluidic system using the same batch of [ 18 F]fluoride, the same microreactor, the same HPLC column and SPE cartridge to obtain a useful production yield. Methods [ 18 F]MEL050, [ 18 F]Fallypride and [ 18 F]PBR111 were radiolabeled with [ 18 F]fluoride using the Advion NanoTek Microfluidic Synthesis System. The outlet of the microreactor was connected to an automated HPLC injector and following the collection of the product, SPE reformulation produced the 18 F-radiotracer in <10% ethanolic saline. A thorough automated cleaning procedure was implemented to ensure no cross-contamination between radiotracer synthesis. Results The complete productions for [ 18 F]MEL050 and [ 18 F]Fallypride were performed at total flow rates of 20 μL/min, resulting in 40 ± 13% and 25 ± 13% RCY respectively. [ 18 F]PBR111 was performed at 200 μL/min to obtain 27 ± 8% RCY. Molar activities for each 18 F-radiotracer were >100 GBq/μmol and radiochemical purities were >97%, implying that the cleaning procedure was effective. Conclusions Using the same initial solution of [ 18 F]fluoride, microreactor, HPLC column and SPE cartridge, three diverse 18 F-radiotracers could be produced in yields sufficient for preclinical studies in a back-to-back fashion using a microfluidic system with no detectable cross-contamination. [ABSTRACT FROM AUTHOR]

During the past decades, extensive efforts have been made to expand the knowledge of amyotrophic lateral sclerosis (ALS). However, clinical translation of this research, in terms of earlier diagnosis and improved therapy, remains challenging. Since more than 30% of motor neurons are lost when symptoms become clinically apparent, techniques allowing non-invasive, in vivo detection of motor neuron degeneration are needed in the early, pre-symptomatic disease stage. Furthermore, it has become apparent that non-motor signs play an important role in the disease and there is an overlap with cognitive disorders, such as frontotemporal dementia (FTD). Radionuclide imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), form an attractive approach to quantitatively monitor the ongoing neurodegenerative processes. Although [F]-FDG has been recently proposed as a potential biomarker for ALS, active targeting of the underlying pathologic molecular processes is likely to unravel further valuable disease information and may help to decipher the pathogenesis of ALS. In this review, we provide an overview of radiotracers that have already been applied in ALS and discuss possible novel targets for in vivo imaging of various pathogenic processes underlying ALS onset and progression. [ABSTRACT FROM AUTHOR]

This review addresses progress in the radionuclide diagnosis of oncological diseases using radiopharmaceutical preparations (RPP) based on labeled glucose derivatives. Most attention is paid to 2-[F]fluoro-2-deoxy-D-glucose (F-FDG), a glucose analog labeled with fluorine-18 ( T = 110 min) and the only radiotracer for glycolysis, which is used in 90% of clinical studies using positron emission tomography (PET). We describe approaches to the synthesis of F-FDG and state-of-the-art automated technologies allowing tens of clinical doses of RPP for PET investigations of patients to be prepared. The main areas of use of PET with F-FDG in the diagnosis of various tumors are discussed, as is the potential for using glucose derivatives with other radionuclides (Ga, I, Tc, Re) as tracers for use in PET and SPECT diagnosis. [ABSTRACT FROM AUTHOR]

Abstract: Breast cancer is a heterogenic cancer being characterized by a variability of somatic mutations and in particular by different receptor expressions, such as estrogen, progesterone and human epidermal receptor. These phenotype characteristics play a crucial role in determining tumour response to various chemotherapies and other treatments and in the development of resistance to therapies. Positron emission tomography (PET) as a nuclear medicine technique, has recently demonstrated the advantages in determining the severity of disease and in evaluating the efficacy of treatments in a variety of neoplasm, including breast cancer. Because this procedure is able to pinpoint molecular activity within the body, it offers the potential to identify disease in its earliest stages as well as a patient’s immediate response to therapeutic interventions in a non-invasive way. In this paper we performed an extended view about the correlation between molecular factors of breast cancer and PET tracers; in particular, we focalized our attention on their possible advantages in terms of 1) early detection of primary or recurrent cancer; 2) as a guide for target therapies and 3) for the evaluation of response to specific and now-available molecular treatments. [Copyright &y& Elsevier]

The use of positron emission tomography for clinical diagnostics has grown rapidly over the past 2 decades. This growth has mainly been due to advances in scanner technology, and particularly the introduction of the combined PET/CT scanner, and has been based almost exclusively on one PET radiopharmaceutical ([F]fluorodeoxyglucose), which is broadly applicable to cancer patients. The availability of radiopharmaceuticals and the clinical diagnostic potential of PET has also supported the continued development of the scanner technology. Due to the efforts of many researchers worldwide in the field of radiopharmaceutical sciences, we are now seeing an increasing number of radiopharmaceuticals used for routine clinical diagnostic imaging. This article is intended as a short educational review, giving a brief overview of the design, preparation and use of PET radiopharmaceuticals, with some examples of highly clinically relevant PET tracers. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The validation and confirmation of clinical usefulness of new and known positron emission tomography (PET) tracers require stable production routes and simple and robust radiochemical procedures. Microfluidic technologies are regarded as an approach that could allow an unprecedented flexibility and productivity in PET radiopharmaceutical research. In this work, we will show how a commercially available microfluidic system can be used for a sequential and repeatable radiosynthesis of three different fluorocholine analogues currently under investigation as tumor tracers. Methods: Advion microfluidic system was used for performing the synthesis and purification of [18F]fluoromethyl, [18F]fluoroethyl or [18F]fluoropropyl choline employing a two-step approach, starting from the corresponding alkyl-ditosylate and reacting the [18F]fluorotosylate obtained in the first step with neat dimethylethanolamine. The purification was obtained using a recyclable SPE cartridge set. Results: The three products, fluoromethylcholine, fluoroethylcholine and fluoropropylcholine, were obtained in good to optimum yields (22%–54% decay corrected) with a 15-min procedure. The production could be restarted several times for producing each one of the tracers without decrease in yields and purities, in accordance with a dose-on-demand (DOD) approach. The final products were formulated in isotonic saline solution. Conclusion: The described approach gives a proof of principle of the enhanced productivity obtainable using a microfluidic approach; in particular, the possibility to produce the reported tracers in a DOD fashion following a homogeneous synthetic and purification approach will foster further studies on the clinical evaluation of the best fluorocholine analogue for prostate cancer imaging without biasing for differences in radiochemical approach. [Copyright &y& Elsevier]

Myocardial perfusion imaging is important for the management of patients with suspected or known coronary artery disease. Nuclear cardiology is the most widely used noninvasive approach for the assessment of myocardial perfusion. The available single-photon emission CT (SPECT) flow agents are characterized by a rapid myocardial extraction and by a cardiac uptake proportional to blood flow. In addition, different positron emission tomography (PET) tracers may be used for the absolute quantitative measurement of myocardial blood flow and coronary flow reserve. However, the available SPECT and PET tracers for myocardial perfusion imaging have some limitations that must be considered to maximize their clinical applications and there is still a well-recognized need for the development of new perfusion tracers with more ideal properties. This review illustrates the current status and the future perspectives of blood flow tracers for SPECT and PET myocardial perfusion imaging. [ABSTRACT FROM AUTHOR]

The increasing demand for radiopharmaceuticals to be provided reproducibly and flexibly with high frequency for clinical application and animal imaging would be better met by improved or even new strategies for automated tracer production. Radiosynthesis in microfluidic systems, i.e. narrow tubing with a diameter of approximately 50–500 μm, holds promise for providing the means for repetitive multidose and multitracer production. In this study, the performance of a conceptually simple microfluidic device integrated into a fully automated synthesis procedure for in-capillary radiosynthesis (ICR) of clinical grade [18F]FDG was evaluated. The instrumental set-up consisted of pumps for reagent and solvent delivery into small mixing chambers, μ-fluidic capillaries, in-process radioactivity monitoring, solid-phase extraction and on-column deprotection of the 18F-labelled intermediate followed by on-line formulation of [18F]FDG. In-capillary18F-fluorination of 2.1 μmol 1,3,4,6-tetra- O-acetyl-2- O-trifluoromethanesulphonyl-beta- d-mannopyranose (TATM; precursor for [18F]FDG) in acetonitrile (MeCN) at a flow rate of 0.3 ml/min within 40 s and subsequent on-line hydrolysis of the intermediate by treatment with 0.3 M NaOH for 1 min at 40°C resulted in a radiochemical yield of 88 ± 4% within <7 min. Reproducibility, robustness and suitability as a fast and efficient radiopharmaceutical research tool for 18F-fluorination was demonstrated by eight independent, sequentially performed ICRs which provided identical tracer quality (radiochemical purity >97%, MeCN <5 μg/ml) and similar absolute yields (approximately 1.4 GBq). The described ICR process is a simple and efficient alternative to classic radiotracer production systems and provides a comparatively cheap instrumental methodology for the repetitive production of [18F]FDG with remarkably high efficiency and high yield under fully automated conditions. Although the results concerning the levels of activity need to be confirmed after installation of the equipment in a suitable GMP hot-cell environment, we expect the instrumental design to allow up-scaling without major difficulties or fundamental restrictions. Furthermore, we are convinced that similar or nearly identical procedures, and thus instrumentation, will allow ICR of other 18F-labelled radiopharmaceuticals. [ABSTRACT FROM AUTHOR]

Activated microglia can be visualised using (R)-[11C]PK11195 (1-[2-chlorophenyl]-N-methyl-N-[1-methyl-propyl]-3-isoquinoline carboxamide) and positron emission tomography (PET). In previous studies, various methods have been used to quantify (R)-[11C]PK11195 binding. The purpose of this study was to determine which parametric method would be best suited for quantifying (R)-[11C]PK11195 binding at the voxel level. Dynamic (R)-[11C]PK11195 scans with arterial blood sampling were performed in 20 healthy and 9 Alzheimer's disease subjects. Parametric images of both volume of distribution (Vd) and binding potential (BP) were obtained using Logan graphical analysis with plasma input. In addition, BP images were generated using two versions of the basis function implementation of the simplified reference tissue model, two versions of Ichise linearisations, and Logan graphical analysis with reference tissue input. Results of the parametric methods were compared with results of full compartmental analysis using nonlinear regression. Simulations were performed to assess accuracy and precision of each method. It was concluded that Logan graphical analysis with arterial input function is an accurate method for generating parametric images of Vd. Basis function methods, one of the Ichise linearisations and Logan graphical analysis with reference tissue input provided reasonably accurate and precise estimates of BP. In pathological conditions with reduced flow rates or large variations in blood volume, the basis function method is preferred because it produces less bias and is more precise.Journal of Cerebral Blood Flow & Metabolism (2007) 27, 1603–1615; doi:10.1038/sj.jcbfm.9600459; published online 21 February 2007 [ABSTRACT FROM AUTHOR]

• SPECT and PET are of great importance for in vivo tracking of immune cells. • Cell tracking technique depends on the type of labeled cell and targeted pathology. • Various radiotracers are used in direct and indirect cell labeling methods. • In the indirect labeling methods, applied radiotracers depend on reporter genes. • The most crucial radiotracers, reporter genes and cell labeling methods are described. There is currently great interest in the development of cell-based therapies, particularly those focused on the idea of exploiting systemically administered immune cells for therapeutic purposes in cancer (e.g. , CAR-T and CAR-NK cells). The ability to monitor the fate of cells in vivo after administration is vital for the assessment of therapeutic outcomes of immune cell-based therapies both in preclinical research and clinical practice. In this context, imaging techniques, which allow for noninvasive and real-time monitoring of the distribution and long-term viability of the adoptively transferred immune cells in the tissue of interest, are of paramount importance. Among clinically relevant in vivo imaging modalities, the nuclear imaging techniques, comprising planar scintigraphy, SPECT, and PET, are considered to be of pivotal importance to in vivo cell tracking and designing optimal treatment strategies for cell-based therapies. This review paper focuses on nuclear imaging and its role in the evaluation of immune cell-based therapies' effectiveness - tracking cells and their ability to home to the target tissue. We compare different types of radiotracers, outline various ways of immune cell labeling, and provide the latest examples for the use of nuclear imaging techniques both in preclinical studies and clinical settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor-associated macrophages (TAMs) play numerous roles in cancer biology and are an important component of the relationship between immune system response and tumor progression. Several new immunotherapy techniques have been developed that target TAMs and are under investigation in both clinical and preclinical settings. Despite this surge of new immunotherapy techniques, a means to specifically and quantifiably measure the presence of TAMs to ensure the viability of these therapies, has yet to be widely investigated. The development of molecular imaging agents that target TAMs provides a path to noninvasively gain valuable insight into the molecular and functional characteristics of the tumor microenvironment and how the immune response facilitates the progression of cancer or therapy response. This article reviews published preclinical and clinical research in the imaging of TAMs through Positron Emission Tomography (PET). Macrophages are large phagocytic cells that can be classified as a type of white blood cell and may be either mobile or stationary in tissues. The presence of macrophages in essentially every major disease makes them attractive candidates to serve as therapeutic targets and diagnostic biomarkers. Macrophages that are found in the microenvironment of solid tumors are referred to as tumor-associated macrophages (TAMs) and have been shown to influence chemoresistance, immune regulation, tumor initiation and tumor growth. The imaging of TAMs through Positron Emission Tomography (PET) has the potential to provide valuable information on cancer biology, tumor progression, and response to therapy. This review will highlight the versatility of macrophage imaging in cancer through the use of PET. [ABSTRACT FROM AUTHOR]

Biomarkers are molecules that are variable in their origin, nature, and mechanism of action; they are of great relevance in biology and also in medicine because of their specific connection with a single or several diseases. Biomarkers are of two types, which in some cases are operative with each other. Fluid biomarkers, started around 2000, are generated in fluid from specific proteins/peptides and miRNAs accumulated within two extracellular fluids, either the central spinal fluid or blood plasma. The switch of these proteins/peptides and miRNAs, from free to segregated within extracellular vesicles, has induced certain advantages including higher levels within fluids and lower operative expenses. Imaging biomarkers, started around 2004, are identified in vivo upon their binding by radiolabeled molecules subsequently revealed in the brain by positron emission tomography and/or other imaging techniques. A positive point for the latter approach is the quantitation of results, but expenses are much higher. At present, both types of biomarker are being extensively employed to study Alzheimer's and other neurodegenerative diseases, investigated from the presymptomatic to mature stages. In conclusion, biomarkers have revolutionized scientific and medical research and practice. Diagnosis, which is often inadequate when based on medical criteria only, has been recently improved by the multiplicity and specificity of biomarkers. Analogous results have been obtained for prognosis. In contrast, improvement of therapy has been limited or fully absent, especially for Alzheimer's in which progress has been inadequate. An urgent need at hand is therefore the progress of a new drug trial design together with patient management in clinical practice. [ABSTRACT FROM AUTHOR]

Target-specific biomolecules, monoclonal antibodies (mAb), proteins, and protein fragments are known to have high specificity and affinity for receptors associated with tumors and other pathological conditions. However, the large biomolecules have relatively intermediate to long circulation half-lives (>day) and tumor localization times. Combining superior target specificity of mAbs and high sensitivity and resolution of the PET (Positron Emission Tomography) imaging technique has created a paradigm-shifting imaging modality, ImmunoPET. In addition to metallic PET radionuclides, 124I is an attractive radionuclide for radiolabeling of mAbs as potential immunoPET imaging pharmaceuticals due to its physical properties (decay characteristics and half-life), easy and routine production by cyclotrons, and well-established methodologies for radioiodination. The objective of this report is to provide a comprehensive review of the physical properties of iodine and iodine radionuclides, production processes of 124I, various 124I-labeling methodologies for large biomolecules, mAbs, and the development of 124I-labeled immunoPET imaging pharmaceuticals for various cancer targets in preclinical and clinical environments. A summary of several production processes, including 123Te(d,n)124I, 124Te(d,2n)124I, 121Sb(α,n)124I, 123Sb(α,3n)124I, 123Sb(3He,2n)124I, natSb(α, xn)124I, natSb(3He,n)124I reactions, a detailed overview of the 124Te(p,n)124I reaction (including target selection, preparation, processing, and recovery of 124I), and a fully automated process that can be scaled up for GMP (Good Manufacturing Practices) production of large quantities of 124I is provided. Direct, using inorganic and organic oxidizing agents and enzyme catalysis, and indirect, using prosthetic groups, 124I-labeling techniques have been discussed. Significant research has been conducted, in more than the last two decades, in the development of 124I-labeled immunoPET imaging pharmaceuticals for target-specific cancer detection. Details of preclinical and clinical evaluations of the potential 124I-labeled immunoPET imaging pharmaceuticals are described here. [ABSTRACT FROM AUTHOR]