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Experimental investigations on novel composite columns with a concrete filled hollow section and high‐strength steel plates as core in ambient and fire conditions High‐performance composite columns are commonly carried out with solid steel sections as core profiles. These profiles imply limitations due to reductions of the yield strength depending on the thickness and high residual stresses. In this publication, the authors present a novel section consisting of a concrete filled circular hollow section with locally connected steel plates as core. To increase the load bearing capacity, steels with yields strengths up to 960 N/mm2 are used. Experimental investigations for ambient conditions and in case of fire are presented. The columns showed a promising load bearing behaviour. These investigations will serve as basis for a systematic development of this innovative, high‐performance composite column with a corresponding design concept. [ABSTRACT FROM AUTHOR]

Assessment of the historic bearings of the Chemnitz viaduct The Chemnitz viaduct was built at the beginning of the 20th century and has been refurbished in recent years in line with its listed status. This required, among other things, an assessment of the reuse of the bearings consisting of individual cast components. The assessment included standard non‐destructive and destructive testing as well as numerical calculations to verify the load‐bearing capacity. As a novel addition, casting simulations, 3D scans of the bearings to record the actual condition and fracture mechanical investigations to assess the risk of brittle fracture and possible crack propagation were carried out. Among other things, difficult accessibility and complex load conditions posed a challenge. This paper presents the bearing concept and the methodology of the assessment and describes the individual components with the associated results. The extensive assessment allowed for the continued use of most of the bearing components. [ABSTRACT FROM AUTHOR]

Abstract: Downstream caspases-3 and -7 are essential to execute the programmed type I cell death (apoptosis). In order to better understand their role, specific inhibitors of these enzymes are required, which after radiolabeling can be applied to non-invasively visualize and monitor apoptotic pathways in vivo using Positron Emission Tomography (PET). Therefore, 2-methoxyethyl-, 2-methoxypropyl-, 2-ethoxymethyl-, 2-(2-fluoroethoxymethyl)-, and 2-(2,2,2-trifluoroethoxymethyl)pyrrolidinyl analogues of (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin (2) were prepared and their in vitro binding affinities towards caspases-1, -3, -6 and -7 were evaluated and compared to that of the lead structure 2. While the inhibition potencies against caspases-1 and -6 were in the micromolar range, all synthesized compounds exhibited excellent and selective inhibition of caspases-3 and -7 in the nanomolar range up to IC50 =4.79nM and 7.47nM, respectively. These highly potent 2-substituted analogues of 2 might be developed as anti-apoptosis agents and some selected fluorinated inhibitors might be useful as potential PET radiotracers for apoptosis imaging after 18F-labeling. [Copyright &y& Elsevier]

The article focuses on the developments on the characterisation of atherosclerotic plaques by medical imaging systems including magnetic resonance imaging (MRI), positron emission tomography (PET) and computed tomography (CT). It states that studies of X-ray CT imaging of atherosclerotic plaques can provide a one-in-all scan to depict plaques. Furthermore, it says that hybrid imaging would combine the strengths of individual methods and compensate for their weaknesses.

The introduction of hybrid imaging modalities such as combined positron emission tomography and computed tomography (PET-CT) has altered image analysis and reporting as well as the expectations of the referring physicians. The training in multimodality imaging is unsatisfactory at the moment because no specialisation is adequate for full analysis of the resulting image data. In the recent “White paper of the European Association of Nuclear Medicine (EANM) and the European Society of Radiology (ESR) on multimodality imaging”, ways to adjust training opportunities and, thus, to improve the situation were proposed. We think that action is urgently required in order to provide optimal training in multimodality imaging. Training in both nuclear medicine and diagnostic radiology should be restructured to allow for optional integrated training in multimodality imaging while maintaining the depth and detail of the individual specialties. We propose criteria for the training in multimodality imaging that can be implemented locally and fast without precluding a yet to be defined regulatory framework. [ABSTRACT FROM AUTHOR]

Inflammation plays an important role in vulnerability of atherosclerotic plaques to rupture and hence acute coronary events. The monocyte–macrophage infiltration in plaques leads to upregulation of cytokines and metalloproteinase enzymes. Matrix metalloproteinases result in matrix dissolution and consequently expansive remodeling of the vessel. They also contribute to attenuation of fibrous cap and hence susceptibility to rupture. Assessment of metalloproteinase expression and activity should provide information about plaque instability. [ABSTRACT FROM AUTHOR]

Inflammation plays an important role in vulnerability of atherosclerotic plaques to rupture and hence acute coronary events. The monocyte–macrophage infiltration in plaques leads to upregulation of cytokines and metalloproteinase enzymes. Matrix metalloproteinases result in matrix dissolution and consequently expansive remodeling of the vessel. They also contribute to attenuation of fibrous cap and hence susceptibility to rupture. Assessment of metalloproteinase expression and activity should provide information about plaque instability. [ABSTRACT FROM AUTHOR]

Purpose: Idiopathic ventricular fibrillation (IVF) is defined as VF in the absence of any identifiable structural or functional cardiac disease. The underlying pathophysiological mechanisms are unknown. This study was performed to investigate the potential impact of sympathetic dysfunction, assessed by 123I-meta-iodobenzylguanidine scintigraphy (123I-MIBG SPECT), on the long-term prognosis of patients with IVF. Methods: 123I-MIBG SPECT was performed in 20 patients (mean age 37±13 years) with IVF. Mean follow-up of patients after study entry was 7.2±1.5 years (range 4.9-10.5 years). Ten patients (five men, five women; mean age 43±12 years; p=NS versus study group) with medullary carcinoma of the thyroid gland served as an age-matched control group. Results: Abnormal 123I-MIBG uptake was observed in 13 patients (65%). During follow-up, 18 episodes of VF/fast polymorphic ventricular tachycardias occurred in four IVF patients with abnormal 123I-MIBG uptake whereas only two episodes of monomorphic ventricular tachycardia (and no VF) occurred in a single IVF patient with normal 123I-MIBG uptake. Conclusion: Impairment of sympathetic innervation may indicate a higher risk of future recurrent episodes of life-threatening ventricular tachyarrhythmias in patients with IVF. Studies in larger cohorts are required to validate the significance of 123I-MIBG SPECT during the long-term follow-up of these patients. [ABSTRACT FROM AUTHOR]

Background: Myocardial hibernation and stunning are characterized by depressed cardiac function in the presence of reduced or normal coronary blood flow. The underlying biochemical mechanisms are widely unknown and only limited data are available in human hearts. Methods and Results: Left ventricular transmural myocardial biopsies were obtained from normal and dysfunctional segments of patients undergoing coronary bypass surgery. Segments were classified as hibernating (n=10) or stunned (n=9) using contrast ventriculography and echocardiography, single photon emission computed tomography (SPECT), and positron emission tomography (PET). In each patient, biopsies from normal myocardial segments were used as controls (n=19). Compared to control myocardium, levels of cAMP (3′-5′cyclic adenosine monophosphate, in fmol/mg wet weight, means±S.E.M.) were higher in hibernating (673±76 versus 518±47, P<0.05) but unchanged in stunned myocardium (513±73 versus 466±97, P>0.05). Protein expression of phospholamban, sarcoendoplasmic Ca2+-ATPase 2a, calsequestrin, the inhibitory subunit of troponin, as well as the activation of p38 MAP kinase were not different when compared to controls. However, heat shock protein 72 (Hsp72) was increased 55% in stunned (2.89±0.58 versus 1.86±0.32, P<0.05) but not in hibernating myocardium (1.68±0.34 versus 1.67±0.29, P>0.05). Conclusions: The data from the present study suggest different pathophysiological mechanisms for myocardial hibernation and stunning. Alterations in the homeostasis of cAMP might be a compensatory mechanism in myocardial hibernation, whereas expression of Hsp72 appears to be cardioprotective in human myocardial stunning. Future studies should further elucidate these mechanisms and their potential impact on future therapeutic interventions. [Copyright &y& Elsevier]

Background: Despite an excellent survival rate, impairments are recognized in the quality of life and emotional well-being of differentiated thyroid cancer (DTC) survivors. Predictors for anxiety and depression in DTC patients are not well characterized. Objective: To identify predictors for anxiety and depression in DTC survivors. Methods: In this cross-sectional study, all DTC survivors presenting for follow-up between 2014 and 2019 in a tertiary referral hospital were asked to complete the "Hospital Anxiety and Depression Scale" (HADS). Depression (HADS-D) and anxiety (HADS-A) subscores were dichotomized for analysis. Univariate and multivariable logistic regression analyses were performed to identify predictors of anxiety and depression. Inverse probability weighting was applied to correct for bias due to nonresponse. Results: Six hundred forty patients meeting study inclusion criteria completed the HADS questionnaire (73% female, mean age 50 years). Of these, 37.6% and 15.7% of patients demonstrated HADS-A and HADS-D scores ≥8. Female sex, elevated body mass index (BMI), permanent recurrent laryngeal nerve damage (RLND), permanent hypoparathyroidism (PH), comorbidities classified in chapter XIX of the International Classification of Diseases, 10th Revision (ICD-10; external causes of morbidity and mortality), and comorbidities in chapter XXI of ICD-10 (factors influencing health status and contact with health services) were independent predictors for elevated anxiety scores with adjusted odds ratios of 1.9 ([CI 1.2–3.2], p < 0.01), 1.0 ([CI 1.0–1.1], p = 0.02), 2.6 ([CI 1.0–6.3], p = 0.04), 2.0 ([CI 1.1–3.5], p = 0.02), 5.5 ([CI 1.0–29.6], p < 0.05), and 1.7 ([CI 1.1–2.6], p = 0.03). PH, elevated anti-Tg titer, comorbidities of the digestive system (chapter XI of ICD-10), and comorbidities of the genitourinary system (chapter XIV of ICD-10) were independent predictors for depression with adjusted odds ratios of 2.2 ([CI 1.2–4.2], p = 0.01), 1.0 ([CI 1.0–1.0], p = 0.04), 3.0 ([CI 1.5–6.1], p < 0.01), and 2.4 ([CI 1.0–5.7], p = 0.04). Conclusions: Female sex, elevated BMI, RLND, PH, and comorbidities classified in chapter XIX and chapter XXI of ICD-10 are predictors for anxiety in DTC patients. PH, elevated anti-Tg titer, comorbidities of the digestive system, and comorbidities of the genitourinary system are predictors for depression in DTC patients. Physicians involved in the follow-up of DTC patients should devote particular attention to the emotional well-being in DTC patients with PH or permanent RLND. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this proof-of-principle study combining data analysis and computer simulation was to evaluate the robustness of apparent diffusion coefficient (ADC) values for lymph node classification in prostate cancer under conditions comparable to clinical practice. Materials and methods: To assess differences in ADC and inter-rater variability, ADC values of 359 lymph nodes in 101 patients undergoing simultaneous prostate-specific membrane antigen (PSMA)-PET/MRI were retrospectively measured by two blinded readers and compared in a node-by-node analysis with respect to lymph node status. In addition, a phantom and 13 patients with 86 lymph nodes were prospectively measured on two different MRI scanners to analyze inter-scanner agreement. To estimate the diagnostic quality of the ADC in real-world application, a computer simulation was used to emulate the blurring caused by scanner and reader variability. To account for intra-individual correlation, the statistical analyses and simulations were based on linear mixed models. Results: The mean ADC of lymph nodes showing PSMA signals in PET was markedly lower (0.77 × 10−3 mm2/s) compared to inconspicuous nodes (1.46 × 10−3 mm2/s, p < 0.001). High inter-reader agreement was observed for ADC measurements (ICC 0.93, 95%CI [0.92, 0.95]). Good inter-scanner agreement was observed in the phantom study and confirmed in vivo (ICC 0.89, 95%CI [0.84, 0.93]). With a median AUC of 0.95 (95%CI [0.92, 0.97]), the simulation study confirmed the diagnostic potential of ADC for lymph node classification in prostate cancer. Conclusion: Our model-based simulation approach implicates a high potential of ADC for lymph node classification in prostate cancer, even when inter-rater and inter-scanner variability are considered. Clinical relevance statement: The ADC value shows a high diagnostic potential for lymph node classification in prostate cancer. The robustness to scanner and reader variability implicates that this easy to measure and widely available method could be readily integrated into clinical routine. Key Points: • The diagnostic value of the apparent diffusion coefficient (ADC) for lymph node classification in prostate cancer is unclear in the light of inter-rater and inter-scanner variability. • Metastatic and inconspicuous lymph nodes differ significantly in ADC, resulting in a high diagnostic potential that is robust to inter-scanner and inter-rater variability. • ADC has a high potential for lymph node classification in prostate cancer that is maintained under conditions comparable to clinical practice. [ABSTRACT FROM AUTHOR]

This document, published in the Journal of Neurology, explores the use of [18F]DPA-714-PET-MRI as a diagnostic tool for autoimmune limbic encephalitis (ALE) with specific autoantibodies. The study involved two patients with these autoantibodies, and the results showed increased tracer uptake in certain areas of the brain. The study suggests that [18F]DPA-714-PET-MRI could be a valuable tool for diagnosing ALE and assessing the immune response in the brain. However, further research is needed to fully understand its potential for clinical use in ALE. [Extracted from the article]

Abstract. Since the human heart has a complex anatomy, the two-dimensional analysis of myocardial scintigrams obviously is not satisfactory. Three-dimensional display can be more easily read by clinicians and depicts more accurately tracer accumulation defects. In this study we propose a three-dimensional myocardial contour detection approach using elastic surfaces. Alter manual reorientation into short-axis slices and transformation into heart coordinates, the myocardial mid-wall surface passing through the radial activity mass points is calculated using a second-order partial differential equation as a mathematical model. Special considerations are implemented to demarcate organs close to the heart. In a total of 1102 myocardial scintigrams the three-dimensional contour detection calculated a reasonable shape of the left ventricular myocardium in all cases. Even in areas with severe myocardial infarction, this approach was able to bridge tracer accumulation defects. Inter- and intra-observer variability tests confirmed a high reproducibility and user independence. In conclusion, in this study the proposed three-dimensional contour detection of left ventricular myocardium using elastic surfaces was found to be fast, user-independent and reliable, leading to realistic three-dimensional parametric images of myocardial scintigrams that even clinicians not experienced in nuclear cardiology can easily read. [ABSTRACT FROM AUTHOR]

Discusses cardiac sympathetic neurotransmission scintigraphy. Details of cardiac neurotransmission; Information on the development of radiopharmaceuticals suitable for investigation of the cardiac nervous system; Cardiac sympathetic neurotransmission scintigraphy inprimary and secondary cardioneuropathies; Role of other imaging techniques for the assessment of cardiac neurotransmission.

For specific imaging of bacterial infections we aimed at targeting the exclusive bacterial iron transport system via siderophore-based radiotracers. De novo synthesis and radiolabeling yielded the salmochelin-based PET radiotracer [68Ga]Ga-RMA693, which showed a favourable biodistribution and a bacteria-specific uptake in an animal model of Escherichia coli infection. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a multisystem disorder of unknown etiology. The leading hypothesis involves an antigen-triggered dysregulated T-cell-driven immunologic response leading to non-necrotic granulomas. In cardiac sarcoidosis (CS), the inflammatory response can lead to fibrosis, culminating in clinical manifestations such as atrioventricular block and ventricular arrhythmias. Cardiac manifestations frequently present as first and isolated signs or may appear in conjunction with extracardiac manifestations. The incidence of sudden cardiac death (SCD) is high. Diagnosis remains a challenge. For a definite diagnosis, endomyocardial biopsy (EMB) is suggested. In clinical practice, compatible findings in advanced imaging using cardiovascular magnetic resonance (CMR) and/or positron emission tomography (PET) in combination with extracardiac histological proof is considered sufficient. Management revolves around the control of myocardial inflammation by employing immunosuppression. However, data regarding efficacy are merely based on observational evidence. Prevention of SCD is of particular importance and several guidelines provide recommendations regarding device therapy. In patients with manifest CS, outcome data indicate a 5-year survival of around 90% and a 10-year survival in the range of 80%. Data for patients with silent CS are conflicting; some studies suggest an overall benign course of disease while others reported contrasting observations. Future research challenges involve better understanding of the immunologic pathogenesis of the disease for a targeted therapy, improving imaging to aid early diagnosis, assessing the need for screening of asymptomatic patients and randomized trials. [ABSTRACT FROM AUTHOR]

Background: Kinetic modelling of dynamic PET typically requires knowledge of the arterial radiotracer concentration (arterial input function, AIF). Its accurate determination is very difficult in mice. AIF measurements in an extracorporeal shunt can be performed; however, this introduces catheter dispersion. We propose a framework for extracorporeal dispersion correction and validated it by comparison to invasively determined intracorporeal AIFs using implanted microprobes. Results: The response of an extracorporeal radiation detector to radioactivity boxcar functions, characterised by a convolution-based dispersion model, gave best fits using double-gamma variate and single-gamma variate kernels compared to mono-exponential kernels for the investigated range of flow rates. Parametric deconvolution with the optimal kernels was performed on 9 mice that were injected with a bolus of 39 ± 25 MBq [18F]F-PSMA-1007 after application of an extracorporeal circulation for three different flow rates in order to correct for dispersion. Comparison with synchronous implantation of microprobes for invasive aortic AIF recordings showed favourable correspondence, with no significant difference in terms of area-under-curve after 300 s and 5000 s. One-tissue and two-tissue compartment model simulations were performed to investigate differences in kinetic parameters between intra- and extracorporeally measured AIFs. Results of the modelling study revealed kinetic parameters close to the chosen simulated values in all compartment models. Conclusion: The high correspondence of simultaneously intra- and extracorporeally determined AIFs and resulting model parameters establishes a feasible framework for extracorporeal dispersion correction. This should allow more precise and accurate kinetic modelling in small animal experiments. [ABSTRACT FROM AUTHOR]

Background: Following resection and standard adjuvant radio- and chemotherapy, approved maintenance therapies for glioblastoma are lacking. Intracavitary radioimmunotherapy (iRIT) with 177Lu-labeled 6A10-Fab fragments targeting tumor-associated carbonic anhydrase XII and injected into the resection cavity offers a novel and promising strategy for improved tumor control. Methods: Three glioblastoma patients underwent tumor resection followed by standard radio- and chemotherapy. These patients with stable disease following completion of standard therapy underwent iRIT on compassionate grounds. After surgical implantation of a subcutaneous injection reservoir with a catheter into the resection cavity, a leakage test with [99mTc]Tc-DTPA was performed to rule out leakage into other cerebral compartments. IRIT comprised three consecutive applications over three months for each patient, with 25%, 50%, 25% of the total activity injected. A dosimetry protocol was included with blood sampling and SPECT/CT of the abdomen to calculate doses for the bone marrow and kidneys as potential organs at risk. Results: All three patients presented without relevant leakage after application of [99mTc]Tc-DTPA. Two patients underwent three full cycles of iRIT (592 MBq and 1228 MBq total activity). One patient showed histologically proven tumor progression after the second cycle (526 MBq total activity). No relevant therapy-associated toxicities or adverse events were observed. Dosimetry did not reveal absorbed doses above upper dose limits for organs at risk. Conclusions: In first individual cases, iRIT with [177Lu]Lu-6A10-Fab appears to be feasible and safe, without therapy-related side effects. A confirmatory multicenter phase-I-trial was recently opened and is currently recruiting. [ABSTRACT FROM AUTHOR]

Simple Summary: Biomarkers reliably predicting treatment response to immune checkpoint inhibition (CKI) therapy in advanced non-small cell lung cancer (NSCLC) are warranted. Baseline 18F-FDG-PET-CT (PET-CT) is an integral part of the diagnostic algorithm of NSCLC. However, there is poor evidence on the predictive and prognostic value of initial PET-CT imaging in these patients. The use of Radiomics has gained prominence in the last decade allowing for the extraction and artificial intelligence-based analysis of additional imaging parameters, so-called radiomic features (RFs). We aimed to find RFs predicting treatment response for CKI-based first-line therapy in advanced NSCLC patients, out of whole-body metabolic PET and morphological CT imaging. PET RFs might additionally be predictive and prognostic and could thus provide important information for future therapy monitoring and guidance. We aimed to evaluate the predictive and prognostic value of baseline 18F-FDG-PET-CT (PET-CT) radiomic features (RFs) for immune checkpoint-inhibitor (CKI)-based first-line therapy in advanced non-small-cell lung cancer (NSCLC) patients. In this retrospective study 44 patients were included. Patients were treated with either CKI-monotherapy or combined CKI-based immunotherapy–chemotherapy as first-line treatment. Treatment response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). After a median follow-up of 6.4 months patients were stratified into "responder" (n = 33) and "non-responder" (n = 11). RFs were extracted from baseline PET and CT data after segmenting PET-positive tumor volume of all lesions. A Radiomics-based model was developed based on a Radiomics signature consisting of reliable RFs that allow classification of response and overall progression using multivariate logistic regression. These RF were additionally tested for their prognostic value in all patients by applying a model-derived threshold. Two independent PET-based RFs differentiated well between responders and non-responders. For predicting response, the area under the curve (AUC) was 0.69 for "PET-Skewness" and 0.75 predicting overall progression for "PET-Median". In terms of progression-free survival analysis, patients with a lower value of PET-Skewness (threshold < 0.2014; hazard ratio (HR) 0.17, 95% CI 0.06–0.46; p < 0.001) and higher value of PET-Median (threshold > 0.5233; HR 0.23, 95% CI 0.11–0.49; p < 0.001) had a significantly lower probability of disease progression or death. Our Radiomics-based model might be able to predict response in advanced NSCLC patients treated with CKI-based first-line therapy. [ABSTRACT FROM AUTHOR]

Structural behaviour of high‐strength composite columns and material behaviour in case of fire Concrete‐filled steel tubular composite columns are increasingly used in enineering practice, as they provide competitive solutions, for buildings with high demands on the load‐bearing capacity and cross‐sectional dimensions. Additionally, composite columns are characterised by high fire resistances. The use of high‐strength materials for composite columns also facilitates the realisation of more sustainable, efficient and economical steel‐concrete composite structures and thus to maintain the long term competitiveness of steel and composite structures. The use of high‐ and ultra‐high‐strength materials for composite columns is currently still limited by the application range of Eurocode 4. The research projects of the HOCHFEST, which are strongly supported by the research association FOSTA, address exactly this limitation and are presented in this issue of Stahlbau. The HOCHFEST research network comprises a total of 15 research projects, which investigate the multiple application potential of high‐strength steels. The research projects P 1287, P 1349, P 1500, P 1501 and P 1502 address the load‐bearing behaviour of high‐performance composite columns and the material behavior of high‐strength steel at ambient temperature as well as in case of fire and under earthquake conditions. The findings of the research projects therefore are essential for the future development of design methods for high‐performance composite columns. [ABSTRACT FROM AUTHOR]

Dysregulated expression or activation of matrix metalloproteinases (MMPs) is observed in many kinds of live-threatening diseases. Therefore, MMP imaging for example with radiolabelled MMP inhibitors (MMPIs) potentially represents a valuable tool for clinical diagnostics using non-invasive single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. This work includes the organic chemical syntheses and in vitro evaluation of five iodinated barbiturate based MMPIs and the selection of derivative 9 for radiosyntheses of isotopologues [123I]9 potentially useful for MMP SPECT imaging and [124I]9 for MMP PET imaging. [ABSTRACT FROM AUTHOR]

Backgrounds: Elastic motion correction in PET has been shown to increase image quality and quantitative measurements of PET datasets affected by respiratory motion. However, little is known on the impact of respiratory motion correction on clinical image evaluation in oncologic PET. This study evaluated the impact of motion correction on expert readers' lymph node assessment of lung cancer patients. Methods: Forty-three patients undergoing F-18-FDG PET/CT for the staging of suspected lung cancer were included. Three different PET reconstructions were investigated: non-motion-corrected ("static"), belt gating-based motion-corrected ("BG-MC") and data-driven gating-based motion-corrected ("DDG-MC"). Assessment was conducted independently by two nuclear medicine specialists blinded to the reconstruction method on a six-point scale s ranging from "certainly negative" (1) to "certainly positive" (6). Differences in s between reconstruction methods, accounting for variation caused by readers, were assessed by nonparametric regression analysis of longitudinal data. From s , a dichotomous score for N1, N2, and N3 ("negative," "positive") and a subjective certainty score were derived. SUV and metabolic tumor volumes (MTV) were compared between reconstruction methods. Results: BG-MC resulted in higher scores for N1 compared to static (p = 0.001), whereas DDG-MC resulted in higher scores for N2 compared to static (p = 0.016). Motion correction resulted in the migration of N1 from tumor free to metastatic on the dichotomized score, consensually for both readers, in 3/43 cases and in 2 cases for N2. SUV was significantly higher for motion-corrected PET, while MTV was significantly lower (all p < 0.003). No significant differences in the certainty scores were noted. Conclusions: PET motion correction resulted in significantly higher lymph node assessment scores of expert readers. Significant effects on quantitative PET parameters were seen; however, subjective reader certainty was not improved. [ABSTRACT FROM AUTHOR]

Hypoxia is an intensively investigated condition with profound effects on cell metabolism, migration, and angiogenesis during development and disease. Physiologically, hypoxia is linked to tissue homeostasis and maintenance of pluripotency. Hypoxia also contributes to pathologies including cardiovascular diseases and cancer. Despite its importance, microscopic visualization of hypoxia is largely restricted to the detection of reductively activated probes by immunostaining. Here, we describe a novel family of genetically encoded fluorescent sensors that detect the activation of HIF transcription factors reported by the oxygenindependent fluorescent protein UnaG. It comprises sensors with different switching and memory behavior and combination sensors that allow the distinction of hypoxic and reoxygenated cells. We tested these sensors on orthotopically transplanted glioma cell lines. Using a cranial window, we could visualize hypoxia intravitally at cellular resolution. In tissue samples, sensor activity was detected in regions, which were largely devoid of blood vessels, correlated with HIF-1α stabilization, and were highly heterogeneous at a cellular level. Frequently, we detected recently reoxygenated cells outside hypoxic areas in the proximity of blood vessels, suggestive of hypoxia-promoted cell migration. [ABSTRACT FROM AUTHOR]

The sphingosine-1-phosphate receptor type 1 (S1P 1 ) is involved in fundamental biological processes such as regulation of immune cell trafficking, vascular barrier function and angiogenesis. This Letter presents multistep syntheses of various fluorine substituted 12-aryl analogues of the drug fingolimod (FTY720) and a seven-steps route to 2-amino-17,17-difluoro-2-(hydroxymethyl)heptadecan-1-ol. In vitro and in vivo tests proved all these compounds as potent S1P 1 receptor agonists. [ABSTRACT FROM AUTHOR]

Introduction: Dysregulated activity of matrix metalloproteinases (MMPs) drives a variety of pathophysiological conditions. Non-invasive imaging of MMP activity in vivo promises diagnostic and prognostic value. However, current targeting strategies by small molecules are typically limited with respect to the bioavailability of the labeled MMP binders in vivo. To this end, we here introduce and compare three chemical modifications of a recently developed barbiturate-based radiotracer with respect to bioavailability and potential to image MMP activity in vivo.Methods: Barbiturate-based MMP inhibitors with an identical targeting unit but varying hydrophilicity were synthesized, labeled with technetium-99m, and evaluated in vitro and in vivo. Biodistribution and radiotracer elimination were determined in C57/BL6 mice by serial SPECT imaging. MMP activity was imaged in a MMP-positive subcutaneous xenograft model of human K1 papillary thyroid tumors. In vivo data were validated by scintillation counting, autoradiography, and MMP immunohistochemistry.Results: We prepared three new 99mTc-labeled MMP inhibitors, bearing either a glycine ([99mTc]MEA39), lysine ([99mTc]MEA61), or the ligand HYNIC with the ionic co-ligand TPPTS ([99mTc]MEA223) yielding gradually increasing hydrophilicity. [99mTc]MEA39 and [99mTc]MEA61 were rapidly eliminated via hepatobiliary pathways. In contrast, [99mTc]MEA223 showed delayed in vivo clearance and primary renal elimination. In a thyroid tumor xenograft model, only [99mTc]MEA223 exhibited a high tumor-to-blood ratio that could easily be delineated in SPECT images.Conclusion: Introduction of HYNIC/TPPTS into the barbiturate lead structure ([99mTc]MEA223) results in delayed renal elimination and allows non-invasive MMP imaging with high signal-to-noise ratios in a papillary thyroid tumor xenograft model. [ABSTRACT FROM AUTHOR]

[Display omitted] • New fluorinated sphingosine-1-phosphate receptor 3 (S1P 3) antagonists have been synthesized. • The most active one was 18F-labelled for application in Positron Emission Tomography (PET) • This compound has good serum stability and medium lipophilicity. • In vivo biodistribution based on PET imaging study in mice showed high uptake in the myocardium. Sphingosine-1-phosphate and its receptors (S1PRs) are involved in several diseases such as auto immunity, inflammation and cardiovascular disorders. The S1P analogue fingolimod (Gilenya®) is currently in use for the treatment of relapsing multiple sclerosis. S1PRs are also promising targets for clinical molecular imaging in vivo. The organ distribution of individual S1PRs can be potentially achieved by using S1PR subtype-specific (radiolabeled) chemical probes. Here, we report our efforts on synthesis and in vivo potency determination of new ligands for the S1P receptor 3 (S1P 3) based on the S1P 3 antagonist TY-52156 and in validation of a potential imaging tracer in vivo using Positron Emission Tomography (PET) after 18F-labelling. A p -fluorophenyl derivative exhibited excellent S1P 3 antagonist activity in vitro , good serum stability, and medium lipophilicity. In vivo biodistribution experiments using 18F-PET exhibited significant uptake in the myocardium suggesting potential applications in cardiac imaging. [ABSTRACT FROM AUTHOR]

Bioorthogonal covalent labeling with self-labeling enzymes like SNAP-tag bears a high potential for specific targeting of cells for imaging in vitro and also in vivo. To this end, fluorescent SNAP substrates have been established and used in microscopy and fluorescence imaging while radioactive substrates for the highly sensitive and whole-body positron emission tomography (PET) have been lacking. Here, we show for the first time successful and high-contrast PET imaging of subcutaneous SNAP-tag expressing tumor xenografts by bioorthogonal covalent targeting with a novel 18F-based radioligand in vivo. [ABSTRACT FROM AUTHOR]

Background: Graft versus host disease (GvHD) is a frequent complication of allogeneic stem cell transplantation (alloSCT), significantly increasing mortality. Previous imaging studies focused on the assessment of intestinal GvHD with contrast-enhanced MRI/CT or 18F-FDG-PET imaging alone. The objective of this retrospective study was to elucidate the diagnostic value of a combined 18F-FDG-PET-MRI protocol in patients with acute intestinal GvHD.Methods: Between 2/2015 and 8/2019, 21 patients with acute intestinal GvHD underwent 18F-FDG-PET-MRI. PET, MRI and PET-MRI datasets were independently reviewed. Readers assessed the number of affected segments of the lower gastrointestinal tract and the reliability of the diagnosis on a 5-point Likert scale and quantitative PET (SUVmax, SUVpeak, metabolic volume (MV)) and MRI parameter (wall thickness), were correlated to clinical staging of acute intestinal GvHD.Results: The detection rate for acute intestinal GvHD was 56.8% for PET, 61.4% for MRI and 100% for PET-MRI. PET-MRI (median Likert-scale value: 5; range: 4-5) offers a significantly higher reliability of the diagnosis compared to PET (median: 4; range: 2-5; p = 0.01) and MRI alone (median: 4; range: 3-5; p = 0.03). The number of affected segments in PET-MRI (rs = 0.677; p <  0.001) and the MV (rs = 0.703; p <  0.001) correlated significantly with the clinical stage. SUVmax (rs = 0.345; p = 0.14), SUVpeak (rs = 0.276; p = 0.24) and wall thickening (rs = 0.174; p = 0.17) did not show a significant correlation to clinical stage.Conclusion: 18F-FDG-PET-MRI allows for highly reliable assessment of acute intestinal GvHD and adds information indicating clinical severity. [ABSTRACT FROM AUTHOR]

Background: Manual quantification of the metabolic tumor volume (MTV) from whole-body 18F-FDG PET/CT is time consuming and therefore usually not applied in clinical routine. It has been shown that neural networks might assist nuclear medicine physicians in such quantification tasks. However, little is known if such neural networks have to be designed for a specific type of cancer or whether they can be applied to various cancers. Therefore, the aim of this study was to evaluate the accuracy of a neural network in a cancer that was not used for its training. Methods: Fifty consecutive breast cancer patients that underwent 18F-FDG PET/CT were included in this retrospective analysis. The PET-Assisted Reporting System (PARS) prototype that uses a neural network trained on lymphoma and lung cancer 18F-FDG PET/CT data had to detect pathological foci and determine their anatomical location. Consensus reads of two nuclear medicine physicians together with follow-up data served as diagnostic reference standard; 1072 18F-FDG avid foci were manually segmented. The accuracy of the neural network was evaluated with regard to lesion detection, anatomical position determination, and total tumor volume quantification. Results: If PERCIST measurable foci were regarded, the neural network displayed high per patient sensitivity and specificity in detecting suspicious 18F-FDG foci (92%; CI = 79–97% and 98%; CI = 94–99%). If all FDG-avid foci were regarded, the sensitivity degraded (39%; CI = 30–50%). The localization accuracy was high for body part (98%; CI = 95–99%), region (88%; CI = 84–90%), and subregion (79%; CI = 74–84%). There was a high correlation of AI derived and manually segmented MTV (R2 = 0.91; p < 0.001). AI-derived whole-body MTV (HR = 1.275; CI = 1.208–1.713; p < 0.001) was a significant prognosticator for overall survival. AI-derived lymph node MTV (HR = 1.190; CI = 1.022–1.384; p = 0.025) and liver MTV (HR = 1.149; CI = 1.001–1.318; p = 0.048) were predictive for overall survival in a multivariate analysis. Conclusion: Although trained on lymphoma and lung cancer, PARS showed good accuracy in the detection of PERCIST measurable lesions. Therefore, the neural network seems not prone to the clever Hans effect. However, the network has poor accuracy if all manually segmented lesions were used as reference standard. Both the whole body and organ-wise MTV were significant prognosticators of overall survival in advanced breast cancer. [ABSTRACT FROM AUTHOR]

Introduction: [177Lu]Lu-PSMA-617 (Lu-PSMA) radioligand therapy is an emerging treatment option for patients with end-stage prostate cancer. However, response to Lu-PSMA therapy is only achieved in approximately half of patients. It is clinically important to identify patients at risk of poor outcome. Therefore, the aim of this study was to evaluate pretherapeutic PSMA PET derived total tumor volume and related metrics as prognosticators of overall survival in patients receiving Lu-PSMA therapy. Methods: A total number of 110 patients form the Departments of Nuclear Medicine Münster and Essen were included in this retrospective analysis. Baseline PSMA PET-CT was available for all patients. Employing a previously published approach, all tumor lesions were semi-automatically delineated in PSMA PET-CT acquisitions. Total lesion number, total tumor volume (PSMA-TV), total lesion uptake (PSMA-TLU = PSMA-TV * SUVmean), and total lesion quotient (PSMA-TLQ = PSMA-TV / SUVmean) were quantified for each patient. Log2 transformation was used for regressions. Results: Lesion number, PSMA-TV, and PSMA-TLQ were prognosticators of overall survival (HR = 1.255, p = 0.009; HR = 1.299, p = 0.005; HR = 1.326, p = 0.002). In a stepwise backward Cox regression including lesion number, PSMA-TV, PSA, LDH, and PSMA-TLQ, only the latter two remained independent and statistically significant negative prognosticators of overall survival (HR = 1.632, p = 0.011; HR = 1.239, p = 0.024). PSMA-TLQ and LDH were significant negative prognosticators in multivariate Cox regression in contrast to PSA value. Conclusion: PSMA-TV was a statistically significant negative prognosticator of overall survival in patients receiving Lu-PSMA therapy. PSMA-TLQ was an independent and superior prognosticator of overall survival compared with PSMA-TV. [ABSTRACT FROM AUTHOR]

Although completely reversible, transient neurological disturbances (grade 1 dizziness, restlessness, anxiety, taste disturbance; grade 2 encephalopathy) caused the patient not to continue therapy after cycle 2 (administered as compassionate use, since continued therapy after CR was not foreseen by the protocol). Treatment strategies in patients with AML or high-risk myelodysplastic syndrome relapsed after allo-SCT. Besides multiple functions in cellular immunity, interleukin 2 (IL2) causes tumour regression.1-5 Proleukine® [aldesleukin, human recombinant IL2 (rhIL2)] was approved for renal cancer and melanoma. Phase I study of F16IL2 antibody-cytokine fusion with very low-dose araC in acute myeloid leukaemia relapse after allogeneic stem cell transplantation. [Extracted from the article]

Surgical resection is the therapy of choice in head and neck paraganglioma but is associated with considerable morbidity. For treatment of inoperable or progressive disease, less aggressive adjuvant options are warranted. This study assessed effectiveness and safety of peptide receptor radionuclide therapy (PRRT) with lutetium-177–DOTATATE for head and neck paraganglioma with emphasis on response assessment. A retrospective analysis of 7 patients with head and neck paraganglioma treated with PPRT between May 2014 and October 2016 was performed. Three patients had jugulotympanic paraganglioma, 3 patients had carotid body tumors, and 1 patient had a combination of both. Patients underwent PRRT after discussion in the local tumor board regarding progressive disease, inoperability, or lack of other adjuvant options. All patients underwent 3–5 cycles of PRRT. Treatment response was evaluated by gallium-68–DOTATATE positron emission tomography/computed tomography and contrast-enhanced computed tomography or magnetic resonance imaging. Outcome measures were two-dimensional tumor diameters and total tumor volumes. Median patient age was 60 years (interquartile range: 14–84 years). All patients had stable disease at posttherapy assessment. Decreasing tumor volumes were found in 4 patients. Clinical symptoms improved in 2 patients. No progression or adverse events occurred during a median follow-up of 39 months (interquartile range: 35–47 months). Somatostatin receptor–targeted therapy using lutetium-177-DOTATATE shows promising effectiveness with a high safety profile. Patients in whom surgical morbidity outweighs oncologic benefit should be informed about PRRT as a treatment option. [ABSTRACT FROM AUTHOR]

Introduction: Efficient therapy of recurrent differentiated thyroid cancer (DTC) is dependent on precise molecular imaging techniques targeting the human sodium iodide symporter (hNIS), which is a marker both of thyroid and DTC cells. Various iodine isotopes have been utilized for detecting DTC; however, these come with unfavorable radiation exposure and image quality ([131I]iodine) or limited availability ([124I]iodine). In contrast, [18F]tetrafluoroborate (TFB) is a novel radiolabeled PET substrate of hNIS, results in PET images with high-quality and low radiation doses, and should therefore be suited for imaging of DTC. The aim of the present study was to compare the diagnostic performance of [18F]TFB-PET to the clinical reference standard [131I]iodine scintigraphy in patients with recurrent DTC. Methods: Twenty-five patients with recurrent DTC were included in this retrospective analysis. All patients underwent [18F]TFB-PET combined with either CT or MRI due to newly discovered elevated TG levels, antiTG levels, sonographically suspicious cervical lymph nodes, or combinations of these findings. Correlative [131I]iodine whole-body scintigraphy (dxWBS) including SPECT-CT was present for all patients; correlative [18F]FDG-PET-CT was present for 21 patients. Histological verification of [18F]TFB positive findings was available in 4 patients. Results: [18F]TFB-PET detected local recurrence or metastases of DTC in significantly more patients than conventional [131I]iodine dxWBS and SPECT-CT (13/25 = 52% vs. 3/25 = 12%, p = 0.002). The diagnosis of 6 patients with cervical lymph node metastases that showed mildly increased FDG metabolism but negative [131I]iodine scintigraphy was changed: [18F]TFB-PET revealed hNIS expression in the metastases, which were therefore reclassified as only partly de-differentiated (histological confirmation present in two patients). Highest sensitivity for detecting recurrent DTC had the combination of [18F]TFB-PET-CT/MRI with [18F]FDG-PET-CT (64%). Conclusion: In the present cohort, [18F]TFB-PET shows higher sensitivity and accuracy than [131I]iodine WBS and SPECT-CT in detecting recurrent DTC. The combination of [18F]TFB-PET with [18F]FDG-PET-CT seems a reasonable strategy to characterize DTC tumor manifestations with respect to their differentiation and thereby also individually plan and monitor treatment. Future prospective studies evaluating the potential of [18F]TFB-PET in recurrent DTC are warranted. [ABSTRACT FROM AUTHOR]

Purpose: Primary angiitis of the central nervous system (PACNS) is a heterogeneous, rare, and poorly understood inflammatory disease. We aimed at non-invasive imaging of activated microglia/macrophages in patients with PACNS by PET-MRI targeting the translocator protein (TSPO) with [18F]DPA-714 to potentially assist differential diagnosis, therapy monitoring, and biopsy planning. Methods: In total, nine patients with ischemic stroke and diagnosed or suspected PACNS underwent [18F]DPA-714-PET-MRI. Dynamic PET scanning was performed for 60 min after injection of 233 ± 19 MBq [18F]DPA-714, and MRI was simultaneously acquired. Results: In two PACNS patients, [18F]DPA-714 uptake patterns exceeded MRI correlates of infarction, whereas uptake was confined to the infarct in four patients where initial suspicion of PACNS could not be confirmed. About three patients with PACNS or cerebral predominant lymphocytic vasculitis showed no or only faintly increased uptake. Short-term [18F]DPA-714-PET follow-up in a patient with PACNS showed reduced lesional [18F]DPA-714 uptake after anti-inflammatory treatment. Biopsy in the same patient pinpointed the source of tracer uptake to TSPO-expressing immune cells. Conclusions: [18F]DPA-714-PET imaging may facilitate the diagnosis and treatment monitoring of PACNS. Further studies are needed to fully understand the potential of TSPO-PET in deciphering the heterogeneity of the disease. [ABSTRACT FROM AUTHOR]

Recently introduced fluorine‑18 prostate‑specific membrane antigen‑1007 ( 18F‑PSMA‑1007) for imaging prostate cancer has an intense physiologic liver uptake and biliary excretion. The aim of the present study was to evaluate the effect of different dietary conditions on this physiological uptake. Forty consecutive prostate cancer patients were scanned with 18F‑PSMA‑1007 positron emission tomography/computed tomography at different dietary conditions. In addition to a blinded read scoring, tracer uptake intensities (standardized uptake values [SUVs]) were measured in the liver and small bowel. There was no significant difference in liver and small‑bowel uptake between different patient groups. Wilcoxon signed‑rank tests revealed no significant difference of the median mean SUV of the liver or maximum SUV of the horizontal part of the duodenum between different dietary conditions groups. A dietary preparation of patients by fasting or the attempt to clear liver activity by high caloric drinks does not have a significant effect on tracer uptake in the liver or in the small bowel. [ABSTRACT FROM AUTHOR]

Purpose: Given the large number of patients with thyroid nodules, improvement of the specificity of current ultrasound-based thyroid nodule classification systems (ATA, EU-TIRADS, and ACR-TIRADS) is warranted to reduce the number of diagnostic thyroidectomies. Thyroid scintigraphy has been shown to demonstrate hyperfunctional nodules, associated with a low malignancy risk, in euthyroid patients. However, it is not known if thyroid scintigraphy could improve specificity of current classification systems. The aim of this study, therefore, was to determine the frequency of hyperfunctional nodules among those nodules in need of fine needle aspiration cytology (FNA) according to current classification systems and to test if nodule functional status is associated with sonographic features. Methods: Five hundred sixty-six euthyroid patients (TSH 0.55–4.20 μU/ml) presenting for thyroid nodule workup including thyroid sonography and scintigraphy at our department between 09/2013 and 02/2018 were included in this retrospective study. All nodules > 10 mm were classified according to ATA, EU-TIRADS, and ACR-TIRADS and correlated to their functional status as assessed by 99mTc-pertechnetate scintigraphy. Results: Ultrasound detected 1029 thyroid nodules ≥ 10 mm, including 545 nodules ≥ 15 mm. Prevalence of hyperfunctional nodules among those with recommendation for FNA according to ATA 2015, EU-TIRADS, and ACR-TIRADS was 6.4%, 6.9%, and 6.5% for nodules ≥ 10 mm and 7.2%, 7.6%, and 7.5% only considering nodules ≥ 15 mm. No sonographic feature was correlated to hyperfunctionality of nodules. Conclusion: In euthyroid patients, thyroid scintigraphy demonstrates hyperfunctionality, which cannot be predicted by ultrasound, in up to 6.9% of nodules in need of FNA according to ultrasound-based classifications. Given the known low risk of malignancy in hyperfunctional nodules, thyroid scintigraphy can lower the frequency of fine needle aspirations and—potentially—the frequency of diagnostic hemithyroidectomies in euthyroid patients. [ABSTRACT FROM AUTHOR]

Background: Respiratory motion in PET/CT leads to well-known image degrading effects commonly compensated using elastic motion correction approaches. Gate-to-gate motion correction techniques are promising tools for improving clinical PET data but suffer from relatively long reconstruction times. In this study, the performance of a fast elastic motion compensation approach based on motion deblurring (DEB-MC) was evaluated on patient and phantom data and compared to an EM-based fully 3D gate-to-gate motion correction method (G2G-MC) which was considered the gold standard. Methods: Twenty-eight patients were included in this study with suspected or confirmed malignancies in the thorax or abdomen. All patients underwent whole-body [18F]FDG PET/CT examinations applying hardware-based respiratory gating. In addition, a dynamic anthropomorphic thorax phantom was studied with PET/CT simulating tumour motion under controlled but realistic conditions. PET signal recovery values were calculated from phantom scans by comparing lesion activities after motion correction to static ground truth data. Differences in standardized uptake values (SUV) and metabolic volume (MV) between both reconstruction methods as well as between motion-corrected (MC) and non motion-corrected (NOMC) results were statistically analyzed using a Wilcoxon signed-rank test. Results: Phantom data analysis showed high lesion recovery values of 91% (2 cm motion) and 98% (1 cm) for G2G-MC and 83% (2 cm) and 90% (1 cm) for DEB-MC. The statistical analysis of patient data found significant differences between NOMC and MC reconstructions for SUV max, SUV mean, MV, and contrast-to-noise ratio (CNR) for both reconstruction algorithms. Furthermore, both methods showed similar increases of 11–12% in SUV max and SUV mean after MC. The statistical analysis of the MC/NOMC ratio found no significant differences between the methods. Conclusion: Both motion correction techniques deliver comparable improvements of SUV max, SUV mean, and CNR after MC on clinical and phantom data. The fast elastic motion compensation technique DEB-MC may thereby be a valuable alternative to state-of-the art motion correction techniques. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The Zn2+-dependent deacetylase LpxC is an essential enzyme in Gram-negative bacteria, which has been validated as antibacterial drug target. Herein we report the chiral-pool synthesis of novel d - and l -proline-derived 3,4-dihydroxypyrrolidine hydroxamates and compare their antibacterial and LpxC inhibitory activities with the ones of 4-monosubstituted and 3,4-unsubstituted proline derivatives. With potent antibacterial activities against several Gram-negative pathogens, the l -proline-based tertiary amine 41g ((S)- N -hydroxy-1-(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)pyrrolidine-2-carboxamide) was found to be the most active antibacterial compound within the investigated series, also showing some selectivity toward EcLpxC (K i = 1.4 μM) over several human MMPs. [ABSTRACT FROM AUTHOR]

Atherosclerotic plaques can remain quiescent for years, but become life threatening upon rupture or disruption, initiating clot formation in the vessel lumen and causing acute myocardial infarction and ischemic stroke. Whether and how a plaque ruptures is determined by its macroscopic structure and microscopic composition. Rupture-prone plaques usually consist of a thin fibrous cap with few smooth muscle cells, a large lipid core, a dense infiltrate of inflammatory cells, and neovessels. Such lesions, termed high-risk plaques, can remain asymptomatic until the thrombotic event. Various imaging technologies currently allow visualization of morphological and biological characteristics of high-risk atherosclerotic plaques. Conventional protocols are often complex and lack specificity for high-risk plaque. Conversely, new imaging approaches are emerging which may overcome these limitations. Validation of these novel imaging techniques in preclinical models of atherosclerosis is essential for effective translational to clinical practice. Imaging the vessel wall, as well as its biological milieu in small animal models, is challenging because the vessel wall is a small structure that undergoes continuous movements imposed by the cardiac cycle as it is adjacent to circulating blood. The focus of this paper is to provide a state-of-the-art review on techniques currently available for preclinical imaging of atherosclerosis in small animal models and to discuss the advantages and limitations of each approach. [ABSTRACT FROM AUTHOR]

Many serious diseases such as cancer, atherosclerosis and arthritis are characterized by upregulation of activated matrix metalloproteinases (MMPs). For this reason imaging and quantification of activated MMPs with the molecular imaging techniques such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) using radiolabeled MMP inhibitors would be a valuable tool for the diagnosis and therapy planning of mentioned diseases. This work aims at the synthesis and preliminary in vitro and in vivo evaluation of positron‐emitter 18F‐fluorine labeled radiotracers based on 2‐{[(4‐phenoxyphenyl)sulfonyl]methyl}thiirane (SB‐3CT), a slow‐binding and mechanism‐based MMP‐2 and −9 inhibitor. Therefore, a library of fluorinated SB‐3CT derivatives were prepared and evaluated in vitro in MMP inhibition assays. From this pool the 18F‐labeled triazole [18F]18d was successfully synthesized in a two‐step procedure. However, this compound was unstable in human and mouse serum and showed a biodistribution behavior in C57BL/6 mice that is not favorable for PET imaging preventing further in vivo evaluations in MMP‐associated mouse models of disease. Imaging of matrix metalloproteinases (MMPs) dysregulated in a multitude of diseases with positron emission tomography (PET) is of great clinical interest. For the first time the thiirane‐based SB‐3CT, exhibiting the unique characteristic of slow‐binding inhibition of MMP‐2 and −9, served as lead structure for 18F‐labeled radiotracer development. The first representative of this compound class ([18F]18d) was evaluated in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Purpose: The introduction of ligands targeting prostate-specific membrane antigen (PSMA), especially 68Ga-PSMA-11, has changed the management of patients with prostate cancer (PCa). 18F-Labelled ligands can be produced in larger amounts and therefore can improve availability for a larger group of patients. The aim of this study was to evaluate the diagnostic performance of the recently introduced 18F-PSMA-1007 in patients with recurrent PCa.Methods: This retrospective analysis included 100 consecutive patients with biochemical relapse (mean age 68.75 ± 7.6 years) referred for PSMA PET/CT. Whole-body PET/CT imaging (from the lower limbs to the skull) was performed in all patients 120 min after injection of 338 ± 44.31 MBq 18F-PSMA-1007. Prostatectomy, radiation beam therapy of the prostate bed and androgen-deprivation therapy had been performed in 92%, 45% and 27% of the patients, respectively. Radiation beam therapy of the prostate bed had been performed in addition to surgery in 38 patients (38%) and 10 patients (10%) had received all three therapy modalities. The probability of a 18F-PSMA-1007 PET/CT scan suggestive of pathology was compared with the Gleason score (GS) and PSA level.Results: Of the 100 patients, 95 (95%) showed at least one pathological finding on 18F-PSMA-1007 PET/CT. The overall median PSA level was 1.34 ng/ml (range 0,04-41.3 ng/ml). The rates of pathological scans were 86%, 89%, 100% and 100% among patients with PSA levels ≤0.5, 0.51-1.0, 1.1-2.0 and > 2.0 ng/ml, respectively. The median GS was 7 (range 5-10). The majority of patients (70) with a GS available had a score in the range 7-9. The rate of pathological scans in these patients was 93% (65/70). The median SUVmax values of the pathological findings were 10.25, 14.32, 13.16 and 28.87 in patients with PSA levels ≤0.5, 0.51-1.0, 1.1-2.0 and >2.0 ng/ml, respectively. The median SUVmax in patients with a PSA level of >2.0 ng/ml was significantly higher than in all other PSA groups.Conclusion: 18F-PSMA-1007 PET/CT can detect recurrent PCa in a high percentage of patients with biochemical relapse. The probability of a pathological 18F-PSMA-1007 PET/CT scan seems to be high even in patients with a low PSA level ≤0.5 ng/ml, and this may have a significant impact on the management of this relevant group of patients. [ABSTRACT FROM AUTHOR]

The unique properties and the usually observed high stability of fluorescent dyes based on BODIPYs ( bo ron dipyrromethin es) predestinate them for application in medicinal chemistry. Depending on the design of the environment of the boron core, a selective 18 F-fluorination is possible. Furthermore, reactive BODIPYs can be used to label bioactive molecules. We synthesized different reactive BODIPYs containing phenyl- and hydroxy substituents on boron as well as mono- and difluorinated counterparts, altering the optical properties of the dyes by rational design of the dipyrromethine ligands. The dyes may directly be used to label bioactive moieties and may be radiolabeled using a previously published protocol. [ABSTRACT FROM AUTHOR]

Purpose: As atherosclerotic plaque ruptures are the primary cause of ischaemic events, their preventive identification by imaging remains a clinical challenge. Matrix metalloproteinases (MMP) are involved in plaque progression and destabilisation and are therefore promising targets to characterize rupture-prone unstable plaques. This study aims at evaluating MMP imaging to discriminate unstable from stable plaque phenotypes. Methods: ApoE deficient mice (ApoE-/-) on a high cholesterol diet underwent implantation of a tapered cuff around the right common carotid artery (CCA) inducing a highly inflamed atherosclerotic plaque upstream (US) and a more stable plaque phenotype downstream (DS) of the cuff. 8 weeks after surgery, the MMP inhibitor-based photoprobe Cy5.5-AF443 was administered i.v. 3h prior to in situ and ex vivo fluorescence reflectance imaging of the CCAs. Thereafter, CCAs were analysed regarding plaque size, presence of macrophages, and MMP-2 and MMP-9 concentrations by immunohistochemistry and ELISA. Results: We found a significantly higher uptake of Cy5.5-AF443 in US as compared to DS plaques in situ (1.29 vs. 1.06 plaque-to-background ratio; p<0.001), which was confirmed by ex vivo measurements. Immunohistochemistry revealed a higher presence of macrophages, MMP-2 and MMP-9 in US compared to DS plaques. Accordingly, MMP-2 concentrations were significantly higher in US plaques (47.2±7.6 vs. 29.6±4.6 ng/mg; p<0.05). Conclusions: In the ApoE-/- cuff model MMP-2 and MMP-9 activities are significantly higher in upstream low shear stress-induced unstable atherosclerotic plaques as compared to downstream more stable plaque phenotypes. MMP inhibitor-based fluorescence molecular imaging allows visualization of these differences in shear stress-induced atherosclerosis. [ABSTRACT FROM AUTHOR]

[Display omitted] • Eighteen N -substituted N -arylsulfonamido d -valines were synthesized and considered for both therapeutic application and medicinal imaging. • Most of these compounds proved to be nanomolar inhibitors particularly for gelatinases MMP-2 and MMP-9. • Generally, the compounds are less potent inhibitors of collagenases (MMP-8 and MMP-13) and macrophage elastase (MMP-12) • Linking a terminal fluoroalkyltriazole moiety at the P1′ substituent did not significantly lower the inhibition potential, but opens an opportunity for 18F-labeling and PET imaging. • Linking a fluorescein moiety (P2′ substituent) at the sulfonamide nitrogen via a triethyleneglycol spacer led to a highly potent probe for fluorescence imaging. To develop matrix metalloproteinase inhibitors (MMPIs) for both therapy and medicinal imaging by fluorescence-based techniques or positron-emission tomography (PET), a small library of eighteen N -substituted N -arylsulfonamido d -valines were synthesized and their potency to inhibit two gelatinases (MMP-2, and MMP-9), two collagenases (MMP-8, and MMP-13) and macrophage elastase (MMP-12) was determined in a Structure-Activity-Relation study with ({4-[3-(5-methylthiophen-2-yl)-1,2,4-oxadiazol-5-yl]phenyl}sulfonyl)- d -valine (1) as a lead. All compounds were shown to be more potent MMP-2/-9 inhibitors (nanomolar range) compared to other tested MMPs. This is a remarkable result considering that a carboxylic acid group is the zinc binding moiety. The compound with a terminal fluoropropyltriazole group at the furan ring (P1′ substituent) was only four times less potent in inhibiting MMP-2 activity than the lead compound 1, making this compound a promising probe for PET application (after using a prosthetic group approach to introduce fluorine-18). Compounds with a TEG spacer and a terminal azide or even a fluorescein moiety at the sulfonylamide N atom (P2′ substituent) were almost as active as the lead structure 1 , making the latter derivative a suitable fluorescence imaging tool. [ABSTRACT FROM AUTHOR]

Purpose: PSMA-targeted PET in patients with prostate cancer (PCa) has a significant impact on treatment decisions. By far the most frequently used PSMA ligand is 68Ga-labelled PSMA-11. However, due to the availability of larger amounts of activity, 18F-labelled PSMA ligands are of major interest. The aim of the present study was to evaluate the biodistribution and performance of the novel 18F-labelled ligand PSMA-1007 at two different time points.Methods: This retrospective analysis included 40 consecutive patients (mean age 68.7 ± 8.1 years) referred for PSMA PET/CT. 18F-PSMA-1007 PET/CT was performed for localization of biochemical relapse, primary staging or therapy follow-up. Circular regions of interest were placed on representative slices of the liver, spleen, kidney, abdominal aortic blood pool, bone marrow (fourth lumbar vertebral body), urinary bladder and gluteus muscle at 60 and 120 min after injection. In malignant lesions the maximum standardized uptake (SUVmax) was measured within volumes of interest at both time points. All SUVs at 60 min were compared with those at 120 min after injection.Results: The activity in the blood pool, urinary bladder and gluteus muscle was very low and decreased significantly over time (P < 0.001). Uptake in the liver, spleen and kidney showed a significant increase over time and uptake in the bone marrow remained stable. Overall, 135 PCa lesions were detected at 60 min and 136 lesions at 120 min after injection. The median SUVmax increased significantly (P < 0.001) from 10.98 to 15.51 between 60 and 120 min.Conclusion: PCa lesions show a significant increase in 18F-PSMA-1007 uptake at 120 min compared with 60 min after injection. In addition, accumulation of the tracer in the urinary bladder was very low leading to improved contrast of adjacent PCa lesions. Increasing accumulation in the liver may limit the sensitivity of the tracer in detecting liver metastases. [ABSTRACT FROM AUTHOR]

Purpose: Non-invasive assessment of inflammatory activity in the course of various diseases is a largely unmet clinical challenge. An early feature of inflammation is local secretion of the alarmin S100A8/A9 by activated phagocytes. We here evaluate a novel S100A9-targeted small molecule tracer Cy5.5-CES271 for in vivo optical imaging of inflammatory activity in exemplary disease models.Procedures: Dynamics of Cy5.5-CES271 was characterized in a model of irritant contact dermatitis by sequential fluorescence reflectance imaging (FRI) up to 24 h postinjection (p.i.). Specificity of Cy5.5-CES271 binding to S100A9 in vivo was examined by blocking studies and by employing S100A9-/- mice. Finally, S100A9 secretion in acute lung inflammation was assessed by Cy5.5-CES271 and FRI of explanted lungs.Results: In ear inflammation, we were able to non-invasively follow the time course of S100A9 expression using Cy5.5-CES271 and FRI over 24 h p.i. (peak activity at 3 h p.i.). Specificity of imaging could be shown by a significant signal reduction after predosing and using S100A9-/- mice. In acute lung injury, local and systemic S100A8/A9 levels increased over time and correlated significantly with FRI signal levels in explanted lungs.Conclusions: Cy5.5-CES271 shows significant accumulation in models of inflammatory diseases and specific binding to S100A9 in vivo. This study, for the first time, demonstrates the potential of a small molecule non-peptidic tracer enabling imaging of S100A9 as a marker of local phagocyte activity in inflammatory scenarios suggesting this compound class for translational attempts. [ABSTRACT FROM AUTHOR]

Dysregulated levels of activated matrix metalloproteinases (MMPs) are linked to different pathologies, such as cancer, atherosclerosis, neuroinflammation, and arthritis. Therefore, imaging of MMPs with positron-emission tomography (PET) represents a powerful tool for the diagnosis of MMP-associated diseases. Moreover, to distinguish between the distinct functions and roles of individual MMPs in particular pathophysiological processes, their specific imaging must be realized with radiolabeled tracers, such as fluorine-18-labeled MMP inhibitors (MMPIs). Therefore, fluorinated dibenzofuransulfonamide-based MMPIs showing excellent inhibition of MMP-12 and selectivity for MMP-12 over other MMPs were prepared. MMP-12 is a key enzyme in diseases such as chronic obstructive pulmonary disease (COPD) and atherosclerosis. Because of their promising in vitro properties, three candidates (4, 9, and 19) were selected from this library, and radiofluorinated analogues ([18F]4, [18F]9, and [18F]19) were successfully synthesized. Initial in vitro serum stability and in vivo biodistribution studies of the radiolabeled MMPIs with PET demonstrated their potential benefit for preferable MMP-12 imaging. [ABSTRACT FROM AUTHOR]

Background Prostate-specific membrane antigen (PSMA) is the up-and-coming target for molecular imaging of prostate cancer. Despite its name, non-prostate-related PSMA expression in physiologic tissue as well as in benign and malignant disease has been reported in various publications. Unlike in prostate cancer, PSMA expression is only rarely observed in non-prostate tumor cells. Instead, expression occurs in endothelial cells of tumor-associated neovasculature, although no endothelial expression is observed under physiologic conditions. The resulting potential for tumor staging in non-prostate malignant tumors has been demonstrated in first patient studies. This review summarizes the first clinical studies and deduces future perspectives in staging, molecular characterization, and PSMA-targeted radionuclide therapy based on histopathologic examinations of PSMA expression. Conclusions The non-exclusivity of PSMA in prostate cancer opens a window to utilize the spectrum of available radioactive PSMA ligands for imaging and molecular characterization and maybe even therapy of non-prostate disease. [ABSTRACT FROM AUTHOR]