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Synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are characterized by the aggregation of α-synuclein. Variations in brain distribution allow for differentiation among these diseases and facilitate precise clinical diagnosis. However, distinguishing between synucleinopathies and Parkinsonism with tauopathies poses a challenge, significantly impacting clinical drug development. Therefore, molecular imaging is crucial for synucleinopathies, particularly for clinical diagnosis, assessment of drug efficacy, and disease surveillance. In recent years, advances in molecular imaging have led to rapid development of α-synuclein-specific tracers for positron emission tomography (PET), most of which are still in pre-clinical stages. Interestingly, some of these tracers share similar compound skeletal structures and are currently undergoing optimization for clinical application. Despite this progress, there remain challenges in developing α-synuclein tracers. This review summarizes recent findings on promising PET tracers and discusses representative compounds' characteristics while offering suggestions for further research orientation. [ABSTRACT FROM AUTHOR]

Purpose: Trophoblast glycoprotein, the so-called 5T4, is an oncofetal antigen expressed in many different cancers. However, no 5T4-specific radioligand is employed in the clinic for non-invasive diagnosis. Thus, the aim of the current study was to develop a PET radiotracer for imaging 5T4 expression in preclinical and clinical stages. Methods: A VHH library was constructed by camel immunization. The specificity of the VHHs toward 5T4 antigen was screened through phage display biopanning and periplasmic extract enzyme-linked immunosorbent assay. 1,4,7-Triazacyclononane-1,4,7-triacetate acid (NOTA) derivative was conjugated to the selected VHH. After radiolabeling, microPET/CT and ex vivo biodistribution were conducted using BxPC-3 and MDA-MB-468 tumor-bearing mice. Cold VHH was co-injected with the tracer to challenge its binding in vivo. For the pilot clinical study, PET/CT images were acquired at 1 h after injection of tracer in patients with pathologically confirmed primary and metastatic tumors. Results: A library with a capacity of 1.2 × 1012 colony-forming units was constructed after successful camel immunization. Nb1-40 with a median effect concentration of 0.43 nM was selected. After humanization, the resulting H006 maintained a high affinity towards 5T4. [68Ga]Ga-NOTA-H006 with the molar activities of 6.48–54.2 GBq/µmol was prepared with high radiochemical purity (> 98%). Using [68Ga]Ga-NOTA-H006, microPET/CT revealed a clear visualization of 5T4 expression in BxPC-3 tumor-bearing mice. Ex vivo biodistribution showed that the highest tumor-to-blood ratio (∼ 3-fold) and tumor-to-muscle ratio (∼ 5-fold) were achieved at 60 min post-injection. Co-injection of the cold H006 at a dose of 1.5 mg/kg significantly reduced the tumor uptake (p < 0.0001). In the pilot clinical study, [68Ga]Ga-NOTA-H006 demonstrated its capacity to map 5T4-positive lesions in humans and yielded a mean effective dose of 3.4 × 10− 2 mSv/MBq. Conclusions: [68Ga]Ga-NOTA-H006, which can visualize 5T4 expression in vivo, has been successfully developed. This opens up opportunities for non-invasively studying 5T4 expression through nuclear medicine. Further clinical investigations are warranted to explore its clinical value in disease progression and companion diagnosis. [ABSTRACT FROM AUTHOR]

Abstract Synucleinopathies, such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, are characterized by the aggregation of α-synuclein. Variations in brain distribution allow for differentiation among these diseases and facilitate precise clinical diagnosis. However, distinguishing between synucleinopathies and Parkinsonism with tauopathies poses a challenge, significantly impacting clinical drug development. Therefore, molecular imaging is crucial for synucleinopathies, particularly for clinical diagnosis, assessment of drug efficacy, and disease surveillance. In recent years, advances in molecular imaging have led to rapid development of α-synuclein-specific tracers for positron emission tomography (PET), most of which are still in pre-clinical stages. Interestingly, some of these tracers share similar compound skeletal structures and are currently undergoing optimization for clinical application. Despite this progress, there remain challenges in developing α-synuclein tracers. This review summarizes recent findings on promising PET tracers and discusses representative compounds’ characteristics while offering suggestions for further research orientation.

Inflammation involves the activation of innate immune cells and is believed to play an important role in the development and progression of both infectious and non-infectious diseases such as neurodegeneration, autoimmune diseases, pulmonary and cancer. Inflammation in the brain is marked by the upregulation of translocator protein (TSPO) in microglia. High TSPO levels are also found, for example, in macrophages in cases of rheumatoid arthritis and in malignant tumor cells compared to their relatively low physiological expression. The same applies for cyclooxgenase-2 (COX-2), which is constitutively expressed in the kidney, brain, thymus and gastrointestinal tract, but induced in microglia, macrophages and synoviocytes during inflammation. This puts TSPO and COX-2 in the spotlight as important targets for the diagnosis of inflammation. Imaging modalities, such as positron emission tomography and single-photon emission tomography, can be used to localize inflammatory processes and to track their progression over time. They could also enable the monitoring of the efficacy of therapy and predict its outcome. This review focuses on the current development of PET and SPECT tracers, not only for the detection of neuroinflammation, but also for emerging diagnostic measures in infectious and other non-infectious diseases such as rheumatic arthritis, cancer, cardiac inflammation and in lung diseases. [ABSTRACT FROM AUTHOR]

Introduction: T cell Ig and ITIM domain receptor (TIGIT) is a next-generation immune checkpoint predominantly expressed on activated T cells and NK cells, exhibiting an unfavorable prognostic association with various malignancies. Despite the emergence of multiple TIGIT-blocking agents entering clinical trials, only a fraction of patients responded positively to anti-TIGIT therapy. Consequently, an urgent demand arises for noninvasive techniques to quantify and monitor TIGIT expression, facilitating patient stratification and enhancing therapeutic outcomes. Small antigen binding moieties such as nanobodies, are promising candidates for such tracer development. Methods: We generated a panel of anti-human or anti-mouse TIGIT nanobodies from immunized llamas. In addition, we designed a single-chain variable fragment derived from the clinically tested monoclonal antibody Vibostolimab targeting TIGIT, and assessed its performance alongside the nanobodies. In vitro characterization studies were performed, including binding ability and affinity to cell expressed or recombinant TIGIT. After Technetium-99m labeling, the nanobodies and the singlechain variable fragment were evaluated in vivo for their ability to detect TIGIT expression using SPECT/CT imaging, followed by ex vivo biodistribution analysis. Results: Nine nanobodies were selected for binding to recombinant and cell expressed TIGIT with low sub-nanomolar affinities and are thermostable. A sixfold higher uptake in TIGIT-overexpressing tumor was demonstrated one hour post- injection with Technetium-99m labeled nanobodies compared to an irrelevant control nanobody. Though the single-chain variable fragment exhibited superior binding to TIGIT-expressing peripheral blood mononuclear cells in vitro, its in vivo behavior yielded lower tumor-to-background ratios at one hour post- injection, indicating that nanobodies are better suited for in vivo imaging than the single-chain variable fragment. Despite the good affinity, high specificity and on-target uptake in mice in this setting, imaging of TIGIT expression on tumor- infiltrating lymphocytes within MC38 tumors remained elusive. This is likely due to the low expression levels of TIGIT in this model. Discussion: The excellent affinity, high specificity and rapid on-target uptake in mice bearing TIGIT- overexpressing tumors showed the promising diagnostic potential of nanobodies to noninvasively image high TIGIT expression within the tumor. These findings hold promise for clinical translation to aid patient selection and improve therapy response. [ABSTRACT FROM AUTHOR]

Background: The occurrence of accidental nerve damage during surgery and the increasing application of image guidance during head-and-neck surgery have highlighted the need for molecular targeted nerve-sparing interventions. The implementation of such interventions relies on the availability of nerve-specific tracers. In this paper, we describe the development of a truncated peptide that has an optimized affinity for protein zero (P0), the most abundant protein in myelin. Methods and Materials: Further C- and N-terminal truncation was performed on the lead peptide Cy5-P0101–125. The resulting nine Cy5-labelled peptides were characterized based on their photophysical properties, P0 affinity, and in vitro staining. These characterizations were combined with evaluation of the crystal structure of P0, which resulted in the selection of the optimized tracer Cy5-P0112–125. A near-infrared Cy7-functionalized derivative (Cy7-P0112–125) was used to perform an initial evaluation of fluorescence-guided surgery in a porcine model. Results: Methodological truncation of the 26-amino-acid lead compound Cy5-P0101–125 resulted in a size reduction of 53.8% for the optimized peptide Cy5-P0112–125. The peptide design and the 1.5-fold affinity gain obtained after truncation could be linked to interactions observed in the crystal structure of the extracellular portion of P0. The near-infrared analogue Cy7-P0112–125 supported nerve illumination during fluorescence-guided surgery in the head-and-neck region in a porcine model. Conclusions: Methodological truncation yielded a second-generation P0-specific peptide. Initial surgical evaluation suggests that the peptide can support molecular targeted nerve imaging. [ABSTRACT FROM AUTHOR]

IntroductionT cell Ig and ITIM domain receptor (TIGIT) is a next-generation immune checkpoint predominantly expressed on activated T cells and NK cells, exhibiting an unfavorable prognostic association with various malignancies. Despite the emergence of multiple TIGIT-blocking agents entering clinical trials, only a fraction of patients responded positively to anti-TIGIT therapy. Consequently, an urgent demand arises for noninvasive techniques to quantify and monitor TIGIT expression, facilitating patient stratification and enhancing therapeutic outcomes. Small antigen binding moieties such as nanobodies, are promising candidates for such tracer development.MethodsWe generated a panel of anti-human or anti-mouse TIGIT nanobodies from immunized llamas. In addition, we designed a single-chain variable fragment derived from the clinically tested monoclonal antibody Vibostolimab targeting TIGIT, and assessed its performance alongside the nanobodies. In vitro characterization studies were performed, including binding ability and affinity to cell expressed or recombinant TIGIT. After Technetium-99m labeling, the nanobodies and the single-chain variable fragment were evaluated in vivo for their ability to detect TIGIT expression using SPECT/CT imaging, followed by ex vivo biodistribution analysis.ResultsNine nanobodies were selected for binding to recombinant and cell expressed TIGIT with low sub-nanomolar affinities and are thermostable. A six-fold higher uptake in TIGIT-overexpressing tumor was demonstrated one hour post- injection with Technetium-99m labeled nanobodies compared to an irrelevant control nanobody. Though the single-chain variable fragment exhibited superior binding to TIGIT-expressing peripheral blood mononuclear cells in vitro, its in vivo behavior yielded lower tumor-to-background ratios at one hour post- injection, indicating that nanobodies are better suited for in vivo imaging than the single-chain variable fragment. Despite the good affinity, high specificity and on-target uptake in mice in this setting, imaging of TIGIT expression on tumor- infiltrating lymphocytes within MC38 tumors remained elusive. This is likely due to the low expression levels of TIGIT in this model.DiscussionThe excellent affinity, high specificity and rapid on-target uptake in mice bearing TIGIT- overexpressing tumors showed the promising diagnostic potential of nanobodies to noninvasively image high TIGIT expression within the tumor. These findings hold promise for clinical translation to aid patient selection and improve therapy response.

Cardiac sarcoidosis (CS) is an inflammatory disease with high morbidity and mortality, with a pathognomonic feature of non-caseating granulomatous inflammation. While 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a well-established modality to image inflammation and diagnose CS, there are limitations to its specificity and reproducibility. Imaging focused on the molecular processes of inflammation including the receptors and cellular microenvironments present in sarcoid granulomas provides opportunities to improve upon FDG-PET imaging for CS. This review will highlight the current limitations of FDG-PET imaging for CS while discussing emerging new nuclear imaging molecular targets for the imaging of cardiac sarcoidosis. [ABSTRACT FROM AUTHOR]

Background: The occurrence of accidental nerve damage during surgery and the increasing application of image guidance during head-and-neck surgery have highlighted the need for molecular targeted nerve-sparing interventions. The implementation of such interventions relies on the availability of nerve-specific tracers. In this paper, we describe the development of a truncated peptide that has an optimized affinity for protein zero (P0), the most abundant protein in myelin. Methods and Materials: Further C- and N-terminal truncation was performed on the lead peptide Cy5-P0101–125. The resulting nine Cy5-labelled peptides were characterized based on their photophysical properties, P0 affinity, and in vitro staining. These characterizations were combined with evaluation of the crystal structure of P0, which resulted in the selection of the optimized tracer Cy5-P0112–125. A near-infrared Cy7-functionalized derivative (Cy7-P0112–125) was used to perform an initial evaluation of fluorescence-guided surgery in a porcine model. Results: Methodological truncation of the 26-amino-acid lead compound Cy5-P0101–125 resulted in a size reduction of 53.8% for the optimized peptide Cy5-P0112–125. The peptide design and the 1.5-fold affinity gain obtained after truncation could be linked to interactions observed in the crystal structure of the extracellular portion of P0. The near-infrared analogue Cy7-P0112–125 supported nerve illumination during fluorescence-guided surgery in the head-and-neck region in a porcine model. Conclusions: Methodological truncation yielded a second-generation P0-specific peptide. Initial surgical evaluation suggests that the peptide can support molecular targeted nerve imaging.

Abstract Background Oncrasin-1 is a small molecule which was identified from a screen of KRAS mutant cancer cells and has shown specificity for KRAS mutant cell killing. We aimed to develop a radiolabelled form of Oncrasin-1 to enable in-vivo imaging of mutant KRAS expression in malignant tumours. This work outlines the synthesis of 3 fluorinated derivatives and development of iodonium salt and boronic ester precursors for radiolabelling with the 18F isotope. Results In our hands, synthesis of iodonium salts were not easily accessible due to the 3-carbaldehyde indole structure being preferentially oxidized by conditions required for iodonium salt formation, rather than benzyl iodide. Synthesis and radiolabelling of boronic acid pinacol ester precursors were successful, with the products being obtained in yields of 10.76% ± 0.96% (n = 5), 14.7% ±8.58% (n = 3) and 14.92% ±3.9% (n = 3) for 18F KAM001, 18F KAM002 and 18F KAM003 respectively, with radiochemical purity of greater than 99%. Conclusions The successful synthesis of these tracers has been undertaken utilizing boronic ester radio-fluorination methods and will allow for investigation of Oncrasin based molecules as potential diagnostics for cancers expressing mutant KRAS protein.

Purpose: Trophoblast glycoprotein, the so-called 5T4, is an oncofetal antigen expressed in many different cancers. However, no 5T4-specific radioligand is employed in the clinic for non-invasive diagnosis. Thus, the aim of the current study was to develop a PET radiotracer for imaging 5T4 expression in preclinical and clinical stages., Methods: A VHH library was constructed by camel immunization. The specificity of the VHHs toward 5T4 antigen was screened through phage display biopanning and periplasmic extract enzyme-linked immunosorbent assay. 1,4,7-Triazacyclononane-1,4,7-triacetate acid (NOTA) derivative was conjugated to the selected VHH. After radiolabeling, microPET/CT and ex vivo biodistribution were conducted using BxPC-3 and MDA-MB-468 tumor-bearing mice. Cold VHH was co-injected with the tracer to challenge its binding in vivo. For the pilot clinical study, PET/CT images were acquired at 1 h after injection of tracer in patients with pathologically confirmed primary and metastatic tumors., Results: A library with a capacity of 1.2 × 10 12 colony-forming units was constructed after successful camel immunization. Nb1-40 with a median effect concentration of 0.43 nM was selected. After humanization, the resulting H006 maintained a high affinity towards 5T4. [ 68 Ga]Ga-NOTA-H006 with the molar activities of 6.48-54.2 GBq/µmol was prepared with high radiochemical purity (> 98%). Using [ 68 Ga]Ga-NOTA-H006, microPET/CT revealed a clear visualization of 5T4 expression in BxPC-3 tumor-bearing mice. Ex vivo biodistribution showed that the highest tumor-to-blood ratio (∼ 3-fold) and tumor-to-muscle ratio (∼ 5-fold) were achieved at 60 min post-injection. Co-injection of the cold H006 at a dose of 1.5 mg/kg significantly reduced the tumor uptake (p < 0.0001). In the pilot clinical study, [ 68 Ga]Ga-NOTA-H006 demonstrated its capacity to map 5T4-positive lesions in humans and yielded a mean effective dose of 3.4 × 10 - 2 mSv/MBq., Conclusions: [ 68 Ga]Ga-NOTA-H006, which can visualize 5T4 expression in vivo, has been successfully developed. This opens up opportunities for non-invasively studying 5T4 expression through nuclear medicine. Further clinical investigations are warranted to explore its clinical value in disease progression and companion diagnosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Vicarious excretion of tracer and contrast media is a known phenomenon and is not fully understood [ 1 , 2 ]. We report a case of unexpected vicarious excretion of 99mTc-pyrophosphate in the gallbladder seen on a scan performed to evaluate suspected cardiac amyloidosis, which is the first report of this phenomenon to the best of our knowledge. [ABSTRACT FROM AUTHOR]

Purpose: Deposition of misfolded alpha-synuclein (αSYN) aggregates in the human brain is one of the major hallmarks of synucleinopathies. However, a target-specific tracer to detect pathological aggregates of αSYN remains lacking. Here, we report the development of a positron emission tomography (PET) tracer based on anle138b, a compound shown to have therapeutic activity in animal models of neurodegenerative diseases. Methods: Specificity and selectivity of [3H]MODAG-001 were tested in in vitro binding assays using recombinant fibrils. After carbon-11 radiolabeling, the pharmacokinetic and metabolic profile was determined in mice. Specific binding was quantified in rats, inoculated with αSYN fibrils and using in vitro autoradiography in human brain sections of Lewy body dementia (LBD) cases provided by the Neurobiobank Munich (NBM). Results: [3H]MODAG-001 revealed a very high affinity towards pure αSYN fibrils (Kd = 0.6 ± 0.1 nM) and only a moderate affinity to hTau46 fibrils (Kd = 19 ± 6.4 nM) as well as amyloid-β1–42 fibrils (Kd = 20 ± 10 nM). [11C]MODAG-001 showed an excellent ability to penetrate the mouse brain. Metabolic degradation was present, but the stability of the parent compound improved after selective deuteration of the precursor. (d3)-[11C]MODAG-001 binding was confirmed in fibril-inoculated rat striata using in vivo PET imaging. In vitro autoradiography showed no detectable binding to aggregated αSYN in human brain sections of LBD cases, most likely, because of the low abundance of aggregated αSYN against background protein. Conclusion: MODAG-001 provides a promising lead structure for future compound development as it combines a high affinity and good selectivity in fibril-binding assays with suitable pharmacokinetics and biodistribution properties. [ABSTRACT FROM AUTHOR]

In contrast to cardiac sympathetic activity which can be assessed with established PET tracers, there are currently no suitable radioligands to measure cardiac parasympathetic (cholinergic) activity. A radioligand able to measure cardiac cholinergic activity would be an invaluable clinical and research tool since cholinergic dysfunction has been associated with a wide array of pathologies (e.g., chronic heart failure, myocardial infarction, arrythmias). [18F]Fluoroethoxybenzovesamicol (FEOBV) is a cholinergic radiotracer that has been extensively validated in the brain. Whether FEOBV PET can be used to assess cholinergic activity in the heart is not known. Hence, this study aimed to evaluate the properties of FEOBV for cardiac PET imaging and cholinergic activity mapping. PET data were collected for 40 minutes after injection of 230 ± 50 MBq of FEOBV in four healthy participants (1 female; Age: 37 ± 10; BMI: 25 ± 2). Dynamic LV time activity curves were fitted with Logan graphical, 1-tissue compartment, and 2-tissue compartment models, yielding similar distribution volume estimates for each participant. Our initial data show that FEOBV PET has favorable tracer kinetics for quantification of cholinergic activity and is a promising new method for assessing parasympathetic function in the heart. [ABSTRACT FROM AUTHOR]

Background: Although N13-ammonia has favorable properties among FDA approved radiotracers, complexity of implementation has limited its use. We describe the initial patient experience of N13-ammonia PET imaging using a compact N13-ammonia production system.Methods: N13 was produced using the ION-12SC, a 12MeV, 10uA superconducting minimally shielded cyclotron, and reduced to N13-ammonia in an automated multi-use purification unit. Patients were power injected with 9.3 ± 1.1 mCi (344.1 ± 40.7 MBq) of N13-ammonia for rest imaging, and 18.8 ± 0.9 mCi (695.6 ± 33.3 MBq) of N13-ammonia was injected at peak hyperemia for stress testing. Images were interpreted for relative perfusion, left ventricular volumes/function, blood flow quantification, and scored for image quality.Results: In total 97 patients underwent 98 N13-ammonia PET scans (32 rest only/65 rest-stress/1 stress only). Image quality was 91.8% good or excellent. None were poor/non-diagnostic. Study durations were acceptable. Tracer related radiation dosimetry to patients was 0.7 ± 0.1 mSv (rest only), and 2.1 ± 0.1 mSv (rest-stress).Conclusion: Clinical N13-ammonia production by the Ionetix ION-12SC delivers high quality myocardial PET perfusion images in a rapid protocol. [ABSTRACT FROM AUTHOR]

Vicarious excretion of tracer and contrast media is a known phenomenon and is not fully understood [1,2]. We report a case of unexpected vicarious excretion of 99m Tc-pyrophosphate in the gallbladder seen on a scan performed to evaluate suspected cardiac amyloidosis, which is the first report of this phenomenon to the best of our knowledge., (Copyright © 2024 American Society of Nuclear Cardiology. Published by Elsevier Inc. All rights reserved.)

Personalized treatment of cancer patients demands specific and validated biomarkers for tumor diagnosis and therapy. The development and validation of such require translational preclinical models that recapitulate human diseases as accurately as possible. Moreover, there is a need for convergence of different (pre)clinical disciplines that openly share their knowledge and methodologies. This review sheds light on the differential perception of biomarkers and gives an overview of currently used models in tracer development and approaches for biomarker discovery.

The understanding of metabolic disease and diabetes on a molecular level has increased significantly due to the recent advances in molecular biology and biotechnology. However, in vitro studies and animal models do not always translate to the human disease, perhaps illustrated by the failure of many drug candidates in the clinical phase. Non-invasive biomedical imaging techniques such as Positron Emission Tomography (PET) offer tools for direct visualization and quantification of molecular processes in humans. Developments in this area potentially enable longitudinal in vivo studies of receptors and processes involved in diabetes guiding drug development and diagnosis in the near future. This mini-review focuses on describing the overall perspective of how PET can be used to increase our understanding and improve treatment of diabetes. The methodological aspects and future developments and challenges are highlighted. [ABSTRACT FROM AUTHOR]

The unique structural architecture of the peptidoglycan allows for the stratification of bacteria as either Gram-negative or Gram-positive, which makes bacterial cells distinguishable from mammalian cells. This classification has received attention as a potential target for diagnostic and therapeutic purposes. Bacteria's ability to metabolically integrate peptidoglycan precursors during cell wall biosynthesis and recycling offers an opportunity to target and image pathogens in their biological state. This Review explores the peptidoglycan biosynthesis for bacteria-specific targeting for infection imaging. Current and potential radiolabeled peptidoglycan precursors for bacterial infection imaging, their development status, and their performance in vitro and/or in vivo are highlighted. We conclude by providing our thoughts on how to shape this area of research for future clinical translation.

The muscarinic cholinergic system regulates peripheral and central nervous system functions, and, thus, their potential as a therapeutic target for several neurodegenerative diseases is undoubted. A clinically applicable positron emission tomography (PET) tracer would facilitate the monitoring of disease progression, elucidate the role of muscarinic acetylcholine receptors (mAChR) in disease development and would aid to clarify the diverse natural functions of mAChR regulation throughout the nervous system, which still are largely unresolved. Still, no mAChR PET tracer has yet found broad clinical application, which demands mAChR tracers with improved imaging properties. This paper reviews strategies of mAChR PET tracer design and summarizes the binding properties and preclinical evaluation of recent mAChR tracer candidates. Furthermore, this work identifies the current major challenges in mAChR PET tracer development and provides a perspective on future developments in this area of research.

Abnormal aggregation of tau in the brain is a major contributing factor in various neurodegenerative diseases. The role of tau phosphorylation in the pathophysiology of tauopathies remains unclear. Consequently, it is important to be able to accurately and specifically target tau deposits in vivo in the brains of patients. The advances of molecular imaging in the recent years have now led to the recent development of promising tau-specific tracers for positron emission tomography (PET), such as THK5317, THK5351, AV-1451, and PBB3. These tracers are now available for clinical assessment in patients with various tauopathies, including Alzheimer's disease, as well as in healthy subjects. Exploring the patterns of tau deposition in vivo for different pathologies will allow discrimination between neurodegenerative diseases, including different tauopathies, and monitoring of disease progression. The variety and complexity of the different types of tau deposits in the different diseases, however, has resulted in quite a challenge for the development of tau PET tracers. Extensive work remains in order to fully characterize the binding properties of the tau PET tracers, and to assess their usefulness as an early biomarker of the underlying pathology. In this review, we summarize recent findings on the most promising tau PET tracers to date, discuss what has been learnt from these findings, and offer some suggestions for the next steps that need to be achieved in a near future. [ABSTRACT FROM AUTHOR]

The cannabinoid type 2 receptor (CB2) has been implicated in a variety of central and peripheral inflammatory diseases, prompting significant interest in the development of CB2-targeted diagnostic and therapeutic agents. A validated positron emission tomography (PET) radioligand for imaging CB2 in the living human brain as well as in peripheral tissues is currently lacking. As part of our research program, we have recently identified the trisubstituted pyridine, [ 18 F]RoSMA-18-d 6 , which proved to be highly suitable for in vitro and in vivo mapping of CB2 in rodents. The aim of this study was to assess the performance characteristics of [ 18 F]RoSMA-18-d 6 in nonhuman primates (NHPs) to pave the way for clinical translation. [ 18 F]RoSMA-18-d 6 was synthesized from the respective tosylate precursor according to previously reported procedures. In vitro autoradiograms with NHP spleen tissue sections revealed a high binding of [ 18 F]RoSMA-18-d 6 to the CB2-rich NHP spleen, which was significantly blocked by coincubation with the commercially available CB2 ligand, GW405833 (10 μM). In contrast, no specific binding was observed by in vitro autoradiography with NHP brain sections, which was in agreement with the notion of a CB2-deficient healthy mammalian brain. In vitro findings were corroborated by PET imaging experiments in NHPs, where [ 18 F]RoSMA-18-d 6 uptake in the spleen was dose-dependently attenuated with 1 and 5 mg/kg GW405833, while no specific brain signal was observed. Remarkably, we observed tracer uptake and retention in the NHP spinal cord, which was reduced by GW405833 blockade, pointing toward a potential utility of [ 18 F]RoSMA-18-d 6 in probing CB2-expressing cells in the bone marrow. If these observations are substantiated in NHP models of enhanced leukocyte proliferation in the bone marrow, [ 18 F]RoSMA-18-d 6 may serve as a valuable marker for hematopoietic activity in various pathologies. In conclusion, [ 18 F]RoSMA-18-d 6 proved to be a suitable PET radioligand for imaging CB2 in NHPs, supporting its translation to humans.

Serotonin 2A receptors have been implicated in various psychophysiological functions and disorders such as depression, Alzheimer's disease, or schizophrenia. Therefore, neuroimaging of this specific receptor is of significant clinical interest, and it is not surprising that many attempts have been made to develop a suitable 5-HT2AR positron emission tomography-tracer. In this review, we give an overview on the precursor, reference compound synthesis, and the preparation of promising 5-HT2AR radiopharmaceuticals applied in positron emission tomography. We also highlight possible learning outcomes that can be made from these tracer development processes. [ABSTRACT FROM AUTHOR]

Purpose: Brain serotonin 6 receptor (5-HT) is one of the most recently identified serotonin receptors. It is a potent therapeutic target for psychiatric and neurological diseases, e.g. schizophrenia and Alzheimer's disease. Since no specific fluorinated radioligand has yet been successfully used to study this receptor by positron emission tomography (PET) neuroimaging, the objective of the present study was to study the first 5-HTF-labelled radiotracer. Methods: 2FNQ1P, inspired by the quinolone core of a previous radiotracer candidate, GSK215083, was selected according its 5-HT affinity and selectivity and was radiolabelled by F nucleophilic substitution. The cerebral distribution of [F]2FNQ1P was studied in vivo in rats, cats and macaque monkeys. Results: The chemical and radiochemical purities of [F]2FNQ1P were >98 %. In rats, in vitro competition with the 5-HT antagonist, SB258585, revealed that the radioligand was displaced dose dependently. Rat microPET studies showed low brain uptake of [F]2FNQ1P, reversed by the P-glycoprotein inhibitor, cyclosporin. On the contrary, PET scans in cats showed good brain penetration and specific striatal binding blocked after pretreatment with unlabelled 2FNQ1P. PET scans in macaque monkeys confirmed high specific binding in both cortical and subcortical regions, specifically decreased by pretreatment with the 5-HT receptor antagonist, SB258585. Conclusion: 2FNQ1P was initially selected because of its suitable characteristics for 5-HT receptor probing in vitro in terms of affinity and specificity. Although in vivo imaging in rats cannot be considered as predictive of the clinical characteristics of the radiotracer, [F]2FNQ1P appeared to be a suitable 5-HT PET tracer in feline and primate models. These preclinical results encourage us to pursue the clinical development of this first fluorinated 5-HT PET radiotracer. [ABSTRACT FROM AUTHOR]

Accurate determination of tumor human epidermal growth factor receptor 2 (HER2)-status in breast cancer patients is possible via noninvasive imaging, provided adequate tracers are used. In this study, we describe the generation of a panel of 38 nanobodies, small HER2-binding fragments that are derived from heavy-chain-only antibodies raised in an immunized dromedary. In search of a lead compound, a subset of nanobodies was biochemically characterized in depth and preclinically tested for use as tracers for imaging of xenografted tumors. The selected compound, 2Rs15d, was found to be stable and to interact specifically with HER2 recombinant protein and HER2-expressing cells in ELISA, surface plasmon resonance, flow cytometry, and radioligand binding studies with low nanomolar affinities, and did not compete with anti-HER2 therapeutic antibodies trastuzumab and pertuzumab. Single-photon-emission computed tomography (SPECT) imaging quantification and biodistribution analyses showed that 99mTc-labeled 2Rs15d has a high tumor uptake in 2 HER2+ tumor models, fast blood clearance, low accumulation in nontarget organs except kidneys, and high concomitant tumor-to-blood and tumor-to-muscle ratios at 1 h after intravenous injection. These values were dramatically lower for an irrelevant control 99mTc-nanobody and for 99mTc-2Rs15d targeting a HER2- tumor. [ABSTRACT FROM AUTHOR]

Purpose: Peptides with restricted conformation provide increased affinity and stability against degradation as compared to linear peptides. This study investigates the characteristics of derivatives of the sunflower trypsin inhibitor 1 (SFTI-1), a 14 amino acid peptide with high intrinsic stability.Methods: Three SFTI-1 derivatives (cyclic cSFTI, acyclic oSFTI, and DOTA-SFTI) were generated by Fmoc-based automated synthesis. Thereafter, the inhibitory activity for trypsin was determined. After radiolabeling, kinetic and competition studies were done in a variety of tumor cell lines including prostate carcinoma, colon carcinoma, mammary carcinoma, and hepatoma to characterize the binding affinity of the peptides. The stability was determined by incubating the molecules in human serum for increasing time periods. Furthermore, the biodistribution was measured in nude mice bearing human prostate carcinomas.Results: The inhibitory constants for trypsin inhibition were 0.08 nM (cSFTI), 0.15 nM (oSFTI), and 0.3 nM (DOTA-SFTI). Among the different tumor cell lines evaluated, the prostate cancer cell lines PC-3 and DU-145 showed the highest accumulation of the radiolabeled peptides. The open-chain derivatives generally bound better than the cyclic one. Binding was constant during 4 h and could be competed by addition of the cold peptide up to 75%. The stability in serum revealed half-lives of 75.8 h for cSFTI, 34.5 h for oSFTI, and 41.7 h for DOTA-SFTI. The biodistribution showed a rapid renal clearance for all three compounds and tumor uptake values up to 3%ID/g.Conclusions: SFTI derivatives are small stable molecules readily accessible by solid-phase synthesis. The trypsin inhibition was not influenced by the cyclization, and addition of a chelator had no significant influence. The exceptional rigidity and stability allow the use of SFTI derivatives as scaffolds for the introduction of tumor-specific peptide motifs which could be used to increase cell-binding affinities and thus their use as diagnostic and/or therapeutic tools. [ABSTRACT FROM AUTHOR]

Personalized treatment of cancer patients demands specific and validated biomarkers for tumor diagnosis and therapy. The development and validation of such require translational preclinical models that recapitulate human diseases as accurately as possible. Moreover, there is a need for convergence of different (pre)clinical disciplines that openly share their knowledge and methodologies. This review sheds light on the differential perception of biomarkers and gives an overview of currently used models in tracer development and approaches for biomarker discovery. [ABSTRACT FROM AUTHOR]

Rapid development of labeling chemistry and generation of new chemical entities for biologic interactions via combinatorial chemistry and high throughput screening gives great potential for the development of new positron emission tomography (PET) tracer candidates. It must, however, be realized that a large fraction of these candidates will fail to characterize the desired biochemistry in vivo due to undesirable properties that are not relevant to providing a specific signal in vitro. A full characterization of a PET tracer is a lengthy and expensive procedure, and it is necessary to establish confidence via a number of assays that a tracer will provide useful data in the target species (generally human). These assays should also serve as a background to choose or to reject a tracer at an early time point, conserving valuable resources and time. Autoradiography performed as an ex vivo binding technique or as ex vivo recording of in vivo tracer distribution are, in this respect, very important tools. Autoradiography binding methods allow a range of frozen tissues to be sectioned and incubated with the PET tracer, and with due caution and controls with selective blockade of binding, quantitative values can be obtained with respect to tracer binding and its regional distribution. The method is easy to learn and set up, and should be included in all PET research and development labs. Ex vivo autoradiography of selected organs or whole animals gives qualitative images of a tracer''s distribution with high resolution and is especially valid for 18F-labeled tracers. When tracer administration is not limited by mass due to specific radioactivity, 11C-tracers can also be readily used. This method is attractive to use as a complement to small animal imaging due to its high resolution and anatomical correlate. Living slice autoradiography is a more cumbersome method, but has an advantage of utilizing live tissue that retains certain metabolic functions. The use of these different methods in the validation of tracers and for supplying complementary information is illustrated. [Copyright &y& Elsevier]

To enable non-invasive real-time quantification of vasopressin 1A (V1A) receptors in peripheral organs, we sought to develop a suitable PET probe that would allow specific and selective V1A receptor imaging in vitro and in vivo. We synthesized a high-affinity and -selectivity ligand, designated compound 17. The target structure was labeled with carbon-11 and tested for its utility as a V1A-targeted PET tracer by cell uptake studies, autoradiography, in vivo PET imaging and ex vivo biodistribution experiments. Compound 17 (PF-184563) and the respective precursor for radiolabeling were synthesized in an overall yield of 49% (over 7 steps) and 40% (over 8 steps), respectively. An inhibitory constant of 0.9 nM towards the V1A receptors was measured, while excellent selectivity over the related V1B, V2 and OT receptor (IC 50 >10,000 nM) were obtained. Cell uptake studies revealed considerable V1A binding, which was significantly reduced in the presence of V1A antagonists. Conversely, there was no significant blockade in the presence of V1B and V2 antagonists. In vitro autoradiography and PET imaging studies in rodents indicated specific tracer binding mainly in the liver. Further, the pancreas, spleen and the heart exhibited specific binding of [11C]17 ([11C]PF-184563) by ex vivo biodistribution experiments. We have developed the first V1A-targeted PET ligand that is suitable for subtype-selective receptor imaging in peripheral organs including the liver, heart, pancreas and spleen. Our findings suggest that [11C]PF-184563 can be a valuable tool to study the role of V1A receptors in liver diseases, as well as in cardiovascular pathologies. [Display omitted] [ABSTRACT FROM AUTHOR]

The muscarinic cholinergic system regulates peripheral and central nervous system functions, and, thus, their potential as a therapeutic target for several neurodegenerative diseases is undoubted. A clinically applicable positron emission tomography (PET) tracer would facilitate the monitoring of disease progression, elucidate the role of muscarinic acetylcholine receptors (mAChR) in disease development and would aid to clarify the diverse natural functions of mAChR regulation throughout the nervous system, which still are largely unresolved. Still, no mAChR PET tracer has yet found broad clinical application, which demands mAChR tracers with improved imaging properties. This paper reviews strategies of mAChR PET tracer design and summarizes the binding properties and preclinical evaluation of recent mAChR tracer candidates. Furthermore, this work identifies the current major challenges in mAChR PET tracer development and provides a perspective on future developments in this area of research. [ABSTRACT FROM AUTHOR]

Background: Oncrasin-1 is a small molecule which was identified from a screen of KRAS mutant cancer cells and has shown specificity for KRAS mutant cell killing. We aimed to develop a radiolabelled form of Oncrasin-1 to enable in-vivo imaging of mutant KRAS expression in malignant tumours. This work outlines the synthesis of 3 fluorinated derivatives and development of iodonium salt and boronic ester precursors for radiolabelling with the 18F isotope. Results: In our hands, synthesis of iodonium salts were not easily accessible due to the 3-carbaldehyde indole structure being preferentially oxidized by conditions required for iodonium salt formation, rather than benzyl iodide. Synthesis and radiolabelling of boronic acid pinacol ester precursors were successful, with the products being obtained in yields of 10.76% ± 0.96% (n = 5), 14.7% ±8.58% (n = 3) and 14.92% ±3.9% (n = 3) for 18F KAM001, 18F KAM002 and 18F KAM003 respectively, with radiochemical purity of greater than 99%. Conclusions: The successful synthesis of these tracers has been undertaken utilizing boronic ester radio-fluorination methods and will allow for investigation of Oncrasin based molecules as potential diagnostics for cancers expressing mutant KRAS protein. [ABSTRACT FROM AUTHOR]

Manganese oxides are an important sink for Ni in the ocean. To explore the potential of Ni stable isotopes as a geochemical tracer, we conducted two types of sorption reactions between Ni and hexagonal birnessite in 0.05 M NaNO 3 media: one where we varied pH from 5 to 8 (constant initial Ni concentration = 170 μmol/L), and a second where we varied the initial dissolved Ni concentration from 17 to 426 μmol/L (constant pH = 7.7). Isotopic measurements were made on both the solid phase and the supernatant solutions to determine the Ni isotope fractionation factors (∆60/58Ni min-aq = δ60/58Ni min − δ60/58Ni aq) between the mineral and aqueous phases. Nickel extended X-ray absorption fine structure (EXAFS) spectroscopy showed Ni in two distinct bonding environments: one where Ni atoms incorporate into the MnO 2 sheet and a second where Ni atoms associate with the mineral surface sharing oxygens with 3 Mn tetrahedra (TCS, triple corner sharing). As pH and net negative surface charge increase, the coordination of Ni shifts to higher proportions of incorporation. The number of structural vacancies in birnessite, which are locations for TCS coordination of Ni, are controlled by pH and increase with decreasing pH. These vacancies are preferentially occupied by lighter Ni isotopes leading to fractionation factors, ∆60/58Ni min-aq , ranging from −2.76‰ (lowest TCS) to −3.35‰ (maximum TCS). These Ni isotopic fractionation factors are among the largest observed in natural geological and biological materials to date. Our findings reveal a relationship between Ni coordination environment and pH that may ultimately be used as an isotopic geochemical tracer of past ocean conditions. However, the results are inconsistent with current isotopic fractionation factors for marine ferromanganese deposits relative to seawater and point to unaddressed processes that modify Ni isotopic fractionation for ferromanganese deposits. Further research is needed to develop Ni as an isotopic tracer. • Manganese oxides are important nickel sink in oceans. • Nickel exists in two distinct chemical bonding environments with manganese oxide birnessite. • Both nickel surface bonding and nickel birnessite mineral incorporation forms exist. • Nickel isotopic fractionation between aqueous phase and solid birnessite occurs. • Future potential for nickel as geochemical tracer of past ocean conditions. [ABSTRACT FROM AUTHOR]

In contrast to cardiac sympathetic activity which can be assessed with established PET tracers, there are currently no suitable radioligands to measure cardiac parasympathetic (cholinergic) activity. A radioligand able to measure cardiac cholinergic activity would be an invaluable clinical and research tool since cholinergic dysfunction has been associated with a wide array of pathologies (e.g., chronic heart failure, myocardial infarction, arrythmias). [ 18 F]Fluoroethoxybenzovesamicol (FEOBV) is a cholinergic radiotracer that has been extensively validated in the brain. Whether FEOBV PET can be used to assess cholinergic activity in the heart is not known. Hence, this study aimed to evaluate the properties of FEOBV for cardiac PET imaging and cholinergic activity mapping. PET data were collected for 40 minutes after injection of 230 ± 50 MBq of FEOBV in four healthy participants (1 female; Age: 37 ± 10; BMI: 25 ± 2). Dynamic LV time activity curves were fitted with Logan graphical, 1-tissue compartment, and 2-tissue compartment models, yielding similar distribution volume estimates for each participant. Our initial data show that FEOBV PET has favorable tracer kinetics for quantification of cholinergic activity and is a promising new method for assessing parasympathetic function in the heart.