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Microfluidic technology is a highly efficient technique used in positron emission tomography (PET) radiochemical synthesis. This approach enables the precise control of reactant flows and reaction conditions, leading to improved yields and reduced synthesis time. The synthesis of two radiotracers, L-[11C]methionine and [11C]choline, was performed, using a microfluidic cassette and an iMiDEVTM module by employing a dose-on-demand approach for the synthesis process. We focused on optimizing the precursor amounts and radiosynthesis on the microfluidic cassette. L-[11C]methionine and [11C]choline were synthesized using a microreactor filled with a suitable resin for the radiochemical reaction. Trapping of the [11C]methyl iodide, its reaction, and solid-phase extraction purification were performed on a microreactor, achieving radiochemical yields of >80% for L-[11C]methionine and >60% for [11C]choline (n = 3). The total synthesis time for both the radiotracers was approximately 20 min. All quality control tests complied with the European Pharmacopeia standards. The dose-on-demand model allows for real-time adaptation to patient schedules, making it suitable for preclinical and clinical settings. Precursor optimization enhanced the cost efficiency without compromising the yield. The importance of dose-on-demand synthesis and optimized precursor utilization to produce L-[11C]methionine and [11C]choline was emphasized in this study. The results demonstrated the feasibility of dose-on-demand adaptations for clinical applications with reduced precursor quantities and high radiochemical yields.

Background The demand for Ga-68-labeled radiotracers has significantly increased in the past decade, driven by the development of diversified imaging tracers, such as FAPI derivatives, PSMA-11, DOTA-TOC, and DOTA-TATE. These tracers have exhibited promising results in theranostic applications, fueling interest in exploring them for clinical use. Among these probes, Ga-68-labeled FAPI-46 and DOTA-TOC have emerged as key players due to their ability to diagnose a broad spectrum of cancers ([Ga-68]Ga-FAPI-46) in late-phase studies, whereas [Ga-68]Ga-DOTA-TOC is clinically approved for neuroendocrine tumors. To facilitate their production, we leveraged a microfluidic cassette-based iMiDEV radiosynthesizer, enabling the synthesis of [Ga-68]Ga-FAPI-46 and [Ga-68]Ga-DOTA-TOC based on a dose-on-demand (DOD) approach.Results Different mixing techniques were explored to influence radiochemical yield. We achieved decay-corrected yield of 44 +/- 5% for [Ga-68]Ga-FAPI-46 and 46 +/- 7% for [Ga-68]Ga-DOTA-TOC in approximately 30 min. The radiochemical purities (HPLC) of [Ga-68]Ga-FAPI-46 and [Ga-68]Ga-DOTA-TOC were 98.2 +/- 0.2% and 98.4 +/- 0.9%, respectively. All the quality control results complied with European Pharmacopoeia quality standards. We optimized various parameters, including Ga-68 trapping and elution, cassette batches, passive mixing in the reactor, and solid-phase extraction (SPE) purification and formulation. The developed synthesis method reduced the amount of precursor and other chemicals required for synthesis compared to conventional radiosynthesizers.Conclusions The microfluidic-based approach enabled the implementation of radiosynthesis of [Ga-68]Ga-FAPI-46 and [Ga-68]Ga-DOTA-TOC on the iMiDEV (TM) microfluidic module, paving the way for their use in preclinical and clinical applications. The microfluidic synthesis approach utilized 2-3 times less precursor than cassette-based conventional synthesis. The synthesis method was also successfully validated in a

This thesis is based on five original articles that investigated the theranostics of prostate cancer by gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) targeting. GRPR and PSMA are two extensively evaluated prostate cancer cell markers due to their overexpression in the majority of prostate cancer samples. Theranostic targeting of GRPR and PSMA is an attractive strategy to improve the management of prostate cancer patients. Papers I and II focused on the dual targeting of GRPR and PSMA. The effect of linker modification on the affinity for GRPR and PSMA and the pharmacokinetic profile was evaluated. In Paper III, the effect of the GRPR antagonist RM26 conjugation to an albumin-binding domain on the pharmacokinetic profile and its potential use in therapy was investigated. Paper IV focused on developing a GRPR antagonist that was suitable for single-photon emission computed tomography (SPECT) using technetium-99m. In Paper V, the GRPR antagonist developed in Paper IV was translated into a phase I clinical trial to assess safety and dosimetry. Modifying the linkers in GRPR and PSMA heterodimers can largely impact the affinity for both targets. This modification influenced the in vivo targeting specificity and biodistribution, with [125I]I-BO530 in Paper I and [111In]In-BQ7812 in Paper II outperforming other analogues. Our findings in Paper III indicated that the conjugation of an albumin-binding domain to RM26 increased the blood concentration of the radiotracer. This increase led to elevated and stable tumour uptake of [111In]In-DOTA-ABD-RM26 after several days of injection. However, [111In]In-DOTA-ABD-RM26 was also increasingly taken up by various healthy organs. The GRPR antagonist [99mTc]Tc-maSSS-PEG2-RM26, studied in Paper IV, showed high specificity and affinity for GRPR. This resulted in elevated GRPR-mediated uptake. Additionally, maSSS-PEG2-RM26 could be radiolabelled via a straightforward radiolabelling protocol. Clini

The understanding of the contribution of the tumour microenvironment to cancer progression and metastasis, in particular the interplay between tumour cells, fibroblasts and the extracellular matrix has grown tremendously over the last years. Lysyl oxidases are increasingly recognised as key players in this context, in addition to their function as drivers of fibrotic diseases. These insights have considerably stimulated drug discovery efforts towards lysyl oxidases as targets over the last decade. This review article summarises the biochemical and structural properties of theses enzymes. Their involvement in tumour progression and metastasis is highlighted from a biochemical point of view, taking into consideration both the extracellular and intracellular action of lysyl oxidases. More recently reported inhibitor compounds are discussed with an emphasis on their discovery, structure-activity relationships and the results of their biological characterisation. Molecular probes developed for imaging of lysyl oxidase activity are reviewed from the perspective of their detection principles, performance and biomedical applications.

The isotopic ratio of two cosmogenic isotopes, ²²Na and ⁷Be, has been recognized as a possible tracer for atmospheric dynamics. We studied how different atmospheric phenomena affect the ²²Na/⁷Be ratio that are known to affect the ground level ⁷Be concentrations. The ²²Na/7Be ratio was studied in the following context: estimation of aerosol residence time, in the intrusions of stratospheric air after Sudden Stratospheric Warming (SSW) events, seasonal variations due to different atmospheric mixing conditions and finally the interannual variations caused by the large-scale atmospheric circulation such as North Atlantic Oscillation (NAO), Arctic Oscillation (AO), Scandinavian Pattern (SCAND) and Quasi-Biennial Oscillation (QBO). This study utilized airborne radioactivity monitoring data from three Finnish stations located in Rovaniemi (66.51 °N, 25.73 °E), Kajaani (64.08 °N, 27.71 °E) and Kotka (60.48 °N, 26.92 °E). The theoretical calculations were performed to see how the ²²Na/⁷Be ratio changes as a function of altitude during when produced by the galactic cosmic rays. The calculations showed that the ²²Na/⁷Be ratio is higher in the stratosphere and lower in the troposphere. At mid-stratosphere level the ratio was 0.001, at tropopause level approximately 0.0007 and at ground level approximately 0.00045. Due to the different half-lives of 22Na and ⁷Be the mean atmospheric residence time can be estimefrom the radioactive decay law by assuming an initial activity concentration ratio of 0.0007 and using the measured ground level ²²Na/⁷Be ratios. This resulted in the median atmospheric residence time as 91–95 days. The atmospheric impact on ²²Na/⁷Be ratio was studied at different time scales starting from short-term impact from SSW, the known seasonal cycle and variations at interannual timescale. SSW events caused rapid increases in the ground level ⁷Be and ²²Na concentrations while the impact on ²²Na/⁷Be ratio was relatively small. A clear seasonal cycle in the

The status of serotonin 5HT2A receptors (5HT2ARs) in schizophrenia has been controversial. In vivo positron emission tomography neuroimaging and in vitro post-mortem binding studies have reported conflicting results about 5HT2AR density. Radiotracers bind different receptor conformations depending on their agonist, antagonist or inverse agonist properties. This study investigates 5HT2AR density in the post-mortem prefrontal cortex from subjects with schizophrenia and controls using three radiotracers with a different pharmacological profile. The specific binding parameters of the inverse agonist [18F]altanserin, the agonist [3 H]lysergic acid diethylamide (LSD) and the antagonist [ 3 H]MDL100907 to brain cortex membranes from 20 subjects with schizophrenia and 20 individually matched controls were evaluated under similar methodological conditions. Ten schizophrenia subjects were antipsychotic-free at death. Saturation curve analyses were performed by non-linear regression to obtain a maximal density of binding sites (Bmax) and the affinity of the respective radiotracers (Kd). In schizophrenia subjects, 5-HT2AR density was decreased when quantified by [18F]altanserin binding, whereas increased when evaluated by [3 H]LSD binding. However, [3 H] MDL100907 binding was unaltered. A slight loss of affinity (higher Kd) was observed exclusively in [3 H]LSD binding. The findings were more evident in antipsychotic-free subjects than in antipsychotic-treated subjects. In conclusion, a higher proportion of the 5-HT2AR-active functional conformation, which is rather identified by agonist radiotracers, was observed in schizophrenia patients. A consequent reduction of the inactive 5-HT2AR conformation, which is preferentially identified by inverse agonist radiotracers, was also obtained. Antagonist radiotracers do not distinguish between molecular conformations of the receptor, and accordingly, the absence of changes was shown. These results are compatible with the proposed increa

Neurological symptoms depend on the topography of the lesions in the nervous system, hence the importance of brain imaging for neurologists. Neurological treatment, however, depends on the biological nature of the lesions. The development of radiotracers specific for the proteinopathies observed in neurodegenerative disorders is, therefore, crucially important for better understanding the relationships between the pathology and the clinical symptoms, as well as the efficacy of therapeutical interventions. The tau protein is involved in several neurodegenerative disorders, that can be distinguished both biologically and clinically as the type of tau isoforms and filaments observed in brain aggregates, and the brain regions affected differ between tauopathies. Over the past few years, several tracers have been developed for imaging tauopathies with positron emission tomography. The present review aims to compare the binding properties of these tracers, with a specific focus on how these properties might be relevant for neurologists using these biomarkers to characterize the pathology of patients presenting with clinical symptoms suspect of a neurodegenerative disorder.

Functional imaging using specific PET-imaging probes plays a key role in diagnosis, staging, treatment planning and monitoring of oncological diseases. Several 68Ga-labelled radiotracers have been applied successfully lately. 68Ga-radionuclide as a positron emitter has an advantage over other radionuclides used in PET radiopharmaceuticals, due to the availability of on-site 68Ge/68Ga generator system without the need of a cyclotron. Moreover, 68Ga radiochemistry and the development of new compounds for radiolabelling with gallium, like DOTA-derivatized peptides have open the door for more researches and applications of 68Ga-labelled radiopharmaceuticals as well as for automating the whole process of radiolabelling. Radiochemistry was and still considering automation of the process of radiopharmaceuticals production an important issue for both researches and clinical applications.In this master thesis, the automated radiolabelling of [68Ga]Ga-DOTANOC, which is used as a radiolabeled somatostatin analog, was evaluated and optimized using a new, fully automated synthesis module (Elysia-Raytest Gaia V2). We aimed to set-up, evaluate and optimize the radiosynthesis protocols for [68Ga]Ga-DOTANOC as well as other radiolabelled DOTA-peptides like [68Ga]Ga-DOTATATE. The radiolabelling of [68Ga]Ga-DOTANOC with Elysia-Raytest Gaia V2 has been performed at three different reaction temperatures, namely 80, 90, and 100 C. and three different reaction times have been tested (6.8 min, 7.8 min, and 8.8 min). Furthermore, another buffer was tested for [68Ga]Ga-DOTANOC radiolabelling with Elysia-Raytest Gaia V2 and lately 5 µL ascorbic acid were added to the radiolabelling mixture to suppress the forming of radioactive side products when using 68Ge/68Ga-generator eluates.The RCP, RCY, and stability of [68Ga]Ga-DOTANOC over time (shelf life) were evaluated and compared to other 68Ga-products with other modules like Raytest Synchrom Research and Scintomics GRP or kit-based radiolabelli

In chemical processes it is essential that the flow in the process is accurately defined. Fluid velocity measurements are important for fluid flow quality performance in flow systems. This study focuses on determination of the volumetric flow rate and its standard (relative) deviation for calibration of conventional flow meters by using a radiotracer approach. The measurements for flow meter calibration were performed at a pilot-scale flow rig using Technetium-99 m (99mTc) as a radiotracer in the form of pertechnetate ion (99mTcO4-). The measured data were analyzed, and precision of the experimental setup was investigated under two different approaches – IAEA’s RTD software and sum approximation of raw data. For the first time, the variation of standard deviation of calculated flow rate with the injection volume and activity of the radiotracer was determined. Plug flow with axial dispersion was used to simulate the measured RTD curves and investigate the flow dynamics of the flowing water. The results of the study have shown the possibility of in situ calibration of flow meters with a relative error lower than 1 %. They also revealed a slight dependency of the precision of output results on the injection volume as well as similar results for manual and specialized RTD software data processing., U hemijskim procesima od suštinskog značaja je tačno definisan i precizan protok. Merenja brzine fluida su važna za karakterizaciju kvaliteta protoka tečnosti u sistemima. Ova studija se fokusira na određivanje zapreminskog protoka i standardnog (relativnog) odstupanja izmerenih vrednosti u cilju kalibracije konvencionalnih merača protoka korišćenjem metode radioaktivnog obeleživača. Merenja potrebna za kalibraciju merača protoka izvedena su na pilot postrojenju korišćenjem Tehnecijuma-99m (99mTc) kao radiotrejsera u obliku pertehnetatnog jona (99mTcO4-). Izmereni podaci su analizirani, a preciznost eksperimentalne postavke je ispitivana pomoću dva različita pristupa: upotrebom softvera za određivanje raspodele vremena zadržavanja (eng. residence time distribution, RTD) koga je razvila Međunarodna agencija za atomsku energiju i zbirne aproksimacije neobrađenih podataka. Po prvi put je utvrđena varijacija standardne devijacije izračunatog protoka u odnosu na zapreminu i u odnosu na aktivnost ubrizganog radioaktivnog obeleživača. Model protoka sa aksijalnom disperzijom je korišćen za simulaciju izmerenih RTD krivih i istraživanje dinamike protoka vode. Rezultati studije su pokazali mogućnost in situ kalibracije merača protoka sa relativnom greškom manjom od 1%. Takođe su pokazali malu zavisnost preciznosti izlaznih rezultata od količine ubrizganog obeleživača, kao i slične rezultate za manuelnu obradu i specijalizovanu obradu podataka upotrebom RTD softvera.

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Cresswell, T., Metian, M., Fisher, N. S., Charmasson, S., Hansman, R. L., Bam, W., Bock, C., & Swarzenski, P. W. Exploring new frontiers in marine radioisotope tracing - adapting to new opportunities and challenges. Frontiers in Marine Science, 7, (2020): 406, doi:10.3389/fmars.2020.00406., Radioisotopes have been used in earth and environmental sciences for over 150 years and provide unique tools to study environmental processes in great detail from a cellular level through to an oceanic basin scale. These nuclear techniques have been employed to understand coastal and marine ecosystems via laboratory and field studies in terms of how aquatic organisms respond to environmental stressors, including temperature, pH, nutrients, metals, organic anthropogenic contaminants, and biological toxins. Global marine issues, such as ocean warming, deoxygenation, plastic pollution, ocean acidification, increased duration, and intensity of toxic harmful algal blooms (HABs), and coastal contamination are all impacting marine environments, thereby imposing various environmental and economic risks. Being able to reliably assess the condition of coastal and marine ecosystems, and how they may respond to future disturbances, can provide vital information for society in the sustainable management of their marine environments. This paper summarizes the historical use of radiotracers in these systems, describes how existing techniques of radioecological tracing can be developed for specific current environmental issues and provides information on emerging issues that would benefit from current and new radiotracer methods. Current challenges with using radioecological tracers and opportunities are highlighted, as well as opportunities to maximize the application of these methods to greatly increase the ability of environmental managers to conduct evidence-based management of coastal and marine ecosystems., The IAEA is grateful for the support provided to its Environment Laboratories by the Government of the Principality of Monaco. This contribution was made within the framework of the IAEA CRP on “Applied radioecological tracers to assess coastal and marine ecosystem health” (K41019).

A major contributor to the occurrence of ischemic stroke is the existence of carotid atherosclerosis. A vulnerable carotid atherosclerotic plaque may rupture or erode, thus causing a thrombotic event. Currently, clinical decision-making with regard to carotid endarterectomy or stenting is still primarily based on the extent of luminal stenosis, estimated with CT angiography and/or (duplex) ultrasonography. However, there is growing evidence that the anatomic impact of stenosis alone has limited value in predicting the exact consequences of plaque vulnerability. Various molecular processes have, independently of degree of stenosis, shown to be importantly associated with the plaque's capability to cause thrombotic events. These molecular processes can be visualized with nuclear medicine techniques allowing the identification of vulnerable patients by non-invasive in vivo SPECT(/CT) and PET(/CT) imaging. This chapter provides an overview of SPECT(/CT) and PET(/CT) imaging with specific radiotracers that have been evaluated for the detection of plaques together with a future perspective in this field of imaging.

In chemical processes it is of essential for flow in the process to be accurate and well defined. Fluid velocity measurements are important for fluid flow quality performance in the systems. This study focuses on determination of volumetric flow rate measurement and on calibration of conventional flowmeter using industrial radiotracer approach. In this work, the application of radiotracer method for RTD measurement in flow meter calibration for chemical industry is described. The experiments in pilot-scale flow rig were performed using Technetium-99 m ( 99mTc) as a radiotracer in the form of pertechnetate ion (99mTcO4 - ) to calibrate flow meter. The data were evaluated using plug flow with axial dispersion model of RTD software. The optimization of the parameters included input signal of radiotracer, concentration of radiotracer and position of detectors. The measured data were analyzed, and precision of experimental setup was investigated under two different approaches. A plug flow with axial dispersion was used to simulate the measured RTD curves and investigate flow dynamics of the flowing water. The results of the study, showed that there might be an optimum injection volume range of the tracer for each specific application. The optimum range in this study was determined from 300 to 700 µL. In this range, relative standard deviation was around 1% for both calculation methods, which is lower than with other available injection volumes. Bias of the initial flow rate was lower using summation approximation, resulting in ca 9% in the area of interest. In case of RTD software, bias values were between 10 and 11%. For the first time the variation of standard deviation of calculated flow rate with injection volume and activity of radiotracer was determined. The results of the study may help in injection volume optimization as well as give a guide on how to process data without RTD software, as the results obtained by both methods were in great agreement. They also rev

Recent studies in neurodegenerative conditions have increasingly highlighted that the same neuropathology can trigger different clinical phenotypes or, vice-versa, that similar phenotypes can be triggered by different neuropathologies. This evidence has called for the adoption of a pathology spectrum-based approach to study neurodegenerative proteinopathies. These conditions share brain deposition of abnormal protein aggregates, leading to aberrant biochemical, metabolic, functional, and structural changes. Positron emission tomography (PET) is a well-recognized and unique tool for the in vivo assessment of brain neuropathology, and novel PET techniques are emerging for the study of specific protein species. Today, key applications of PET range from early research and clinical diagnostic tools to their use in clinical trials for both participants screening and outcome evaluation. This position article critically reviews the role of distinct PET molecular tracers for different neurodegenerative proteinopathies, highlighting their strengths, weaknesses, and opportunities, with special emphasis on methodological challenges and future applications.

Introduction: A rapid transition from a clinical-based classification to a pathology-based classification of neurodegenerative conditions, largely promoted by the increasing availability of imaging biomarkers, is emerging. The Framework for Innovative Multi-tracer molecular Brain Imaging, funded by the EU Joint Program - Neurodegenerative Disease Research 2016 “Working Groups for Harmonisation and Alignment in Brain Imaging Methods for Neurodegeneration,” aimed at providing a roadmap for the applications of established and new molecular imaging techniques in dementia. Methods: We consider current and future implications of adopting a pathology-based framework for the use and development of positron emission tomography techniques. Results: This approach will enhance efforts to understand the multifactorial etiology of Alzheimer's disease and other dementias. Discussion: The availability of pathology biomarkers will soon transform clinical and research practice. Crucially, a comprehensive understanding of strengths and caveats of these techniques will promote an informed use to take full advantage of these tools.

Background: Bacterial infections are still a major global healthcare problem. To combat the increasing antimicrobial resistance, early diagnosis of bacterial infections—including the identification of bacterial species—is needed to improve antibiotic stewardship and to help reduce the use of broad-spectrum antibiotics. To aid successful targeted antibiotic treatment, specific detection and localisation of infectious organisms is warranted. Nuclear medicine imaging approaches have been successfully used to diagnose bacterial infections and to differentiate between pathogen induced infections and sterile inflammatory processes. Aim: In this comprehensive review we present an overview of recent developments in radiolabelled bacterial imaging tracers. Methods: The PubMed/MEDLINE and Embase (OvidSP) literature databases were systematically searched for publications on SPECT and PET on specific imaging of bacterial using specific guidelines with MeSH-terms, truncations, and completion using cross-references. Tracers in literature that was extensively reviewed before 2016 were not included in this update. Where possible, the chemical structure of the radiolabelled compounds and clinical images were shown. Results: In 219 original articles pre-clinical and clinical imaging of bacterial infection with new tracers were included. In our view, the highest translational potential lies with tracers that are specific to target the pathogens: e.g., 99m Tc- and 68 Ga-labelled UBI 29–41 , 99m Tc-vancomycin, m-[ 18 F]-fluoro-PABA, [methyl- 11 C]-D-methionine, [ 18 F]-FDS, [ 18 F]-maltohexaose and [ 18 F]-maltotriose. An encouraging note is that some of these tracers have already been successfully evaluated in clinical settings. Conclusion: This review summarises updates in tracer development for specific (pre-clinical and clinical) imaging of bacterial infections. We propsed some promising tracers that are likely to become innovative standards in the clinical setting in the near featu

Introduction: A rapid transition from a clinical-based classification to a pathology-based classification of neurodegenerative conditions, largely promoted by the increasing availability of imaging biomarkers, is emerging. The Framework for Innovative Multi-tracer molecular Brain Imaging, funded by the EU Joint Program - Neurodegenerative Disease Research 2016 “Working Groups for Harmonisation and Alignment in Brain Imaging Methods for Neurodegeneration,” aimed at providing a roadmap for the applications of established and new molecular imaging techniques in dementia. Methods: We consider current and future implications of adopting a pathology-based framework for the use and development of positron emission tomography techniques. Results: This approach will enhance efforts to understand the multifactorial etiology of Alzheimer's disease and other dementias. Discussion: The availability of pathology biomarkers will soon transform clinical and research practice. Crucially, a comprehensive understanding of strengths and caveats of these techniques will promote an informed use to take full advantage of these tools.

Breast cancer (BC) is the 2nd most common cancer worldwide and the most frequent cancer type occurring in women. The disease is highly heterogeneous consisting of various subtypes; and therapy and prognosis varies dependent on the BC subtype. Unfortunately, the currently used methods for BC imaging have limitations and current treatments for metastatic disease are unfortunately not associated with cure. Within nuclear medicine peptide receptor-mediated imaging and therapy using radioligands is clinically successfully used for imaging and treatment of neuroendocrine tumors. Ideally the same ligand is used for both imaging and treatment, the so called theranostic approach. Next to neuroendocrine tumors, this imaging and therapy method is under investigation for imaging and treatment of other cancer types as well. Concerning BC, overexpression of targets for which suitable radiotracers are available have been described. The aim of the studies described in this thesis was to investigate the application of these radiotracers for theranostic purposes in BC, with the ultimate goal of improving BC patient care. The main focus was on targeting the gastrin releasing peptide receptor (GRPR) and somatostatin receptor subtype 2 (SSTR2), and to a lesser extent c-x-c chemokine receptor 4 (CXCR4), with radiotracers for both imaging and treatment. The thesis is divided in 4 parts: Part 1 gives an introduction on the relevant subjects and provides an overview of receptor-targeted nuclear imaging of BC, part 2 focusses on the clinical relevance of targeting GRPR, SSTR2 and CXCR4 and part 3 and part 4 are focussed on targeting of SSTR2 and GRPR, respectively. All studies described in this thesis were performed in a preclinical setting.

A series of vasopressin receptor V1a ligands have been synthesized for positron emission tomography (PET) imaging. The lead compound (1S,5R)-1 ((4-(1H-indol-3-yl)-3-methoxyphenyl) ((1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone) and its F-ethyl analog 6c exhibited the best combination of high binding affinity and optimal lipophilicity within the series. (1S,5R)-1 was radiolabeled with 11C for PET studies. [11CH3](1S,5R)-1 readily entered the mouse (4.7% ID/g tissue) and prairie vole brains (∼2% ID/g tissue) and specifically (30-34%) labeled V1a receptor. The common animal anesthetic Propofol significantly blocked the brain uptake of [11CH3](1S,5R)-1 in the mouse brain, whereas anesthetics Ketamine and Saffan increased the uptake variability. Future PET imaging studies with V1a radiotracers in non-human primates should be performed in awake animals or using anesthetics that do not affect the V1a receptor.

Many of modern diagnostic methods cannot be achieved without radioisotopes. In this review, an overview of the most common radioisotopes (radionuclides) used as markers for in vitro and in vivo studies is provided. To determine the extremely low concentrations of some biological molecules (hormones, drugs, toxins, nucleic acid, etc.) in biological fluids for in vitro studies, β and/or γ emitters with different half-lives: H-3, C-14, P-32, P-33, I-125, Cr-51 were frequently used. The majority of all radionuclides (90 %) were utilized for in vivo diagnostics. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are imaging modalities widely used in diagnostic nuclear medicine. The most important diagnostic radionuclides are technetium-99m (for single photon emission computed tomography) and fluorine-18 (for positron emission tomography).

Diabetes is a rapidly growing disease with 415 million affected adults worldwide. The pancreatic endocrine cells, most importantly the insulin producing β-cells, play an important role in regulating blood glucose homeostasis. Type 1 diabetes (T1D) is characterized by the inability of the pancreas to secrete sufficient amounts of insulin due to autoimmune destruction of insulin producing β-cells. Type 2 diabetes (T2D) on the other hand is characterized by defects in insulin secretion and insulin sensitivity. Alterations in the β-cell mass (BCM) and/or function play a major role in the development and progression of the disease. Understanding BCM dynamics in disease models is therefore a key aspect for better interpretation of research results. In this thesis, we have used optical projection tomography (OPT) as a tool to evaluate a non-invasive imaging modality for β-cell scoring and to study disease dynamics in frequently used animal models for T1D and T2D. The possibility to monitor BCM in vivo would radically improve our competence in studying the pathogenesis of diabetes and in therapeutic interventions. Single photon emission computed tomography (SPECT) is a widely used technique that has become a promising approach to monitor changes in BCM in vivo. A key issue for using this approach is to evaluate the β-cell specificity and read out of the utilized radiotracers. This is most commonly performed by conventional stereological approaches, which rely on the extrapolation of 2D data. We developed a protocol for SPECT-OPT multimodal imaging that enables rapid and accurate cross evaluation of SPECT based assessments of BCM. While histological determination of islet spatial distribution was challenging, SPECT and OPT revealed similar distribution patterns of the radiotracer 111In-exendin-3 and insulin positive β-cell volumes respectively between different pancreatic lobes, both visually and quantitatively. We propose SPECT-OPT multimodal imaging as an accurate and bett

This study aims at analysing the latitudinal variability of both the yearly and seasonal pattern of Be-7 surface activity concentrations, at addressing the impact of tropopause height (TPH) on Be-7 distribution and at evaluating the time lag between TPH and Be-7 at European level. With this aim, weekly Be-7 and daily TPH data at 17 sampling stations during 10 yr (2001-2010) are analysed. Be-7 shows a clear increasing tendency in the period and generally tends to increase with decreasing latitude. The seasonal pattern generally shows maxima during the warm period and minima during the cold one. The seasonal variogram analysis points out a good spatial correlation for TPH data while a weaker one is observed for Be-7, having TPH a larger influence on Be-7 during summer. The influence of TPH on Be-7 exhibits a large spatial variability, with a clear gap between south and north in the area of the polar front jet. The results identify the presence of two main groups, in particular separating between stations located in northern Europe (50 degrees N and higher) and stations in southern Europe (south of 50 degrees N). A similar behaviour for stations located in the same geographical area is also observed when looking at the day of maximum impact of TPH on Be-7 concentrations. The results suggest that Be-7 concentrations respond in different time ranges to changes in the TPH, observing seasonal differences in each group. These results represent the first European approach to the understanding of the TPH impact on Be-7 concentrations at surface levels.

This review focuses on the chemistry and application of radium isotopes to environmental monitoring, analytical, and medicinal uses. In recent years, radium has been used primarily as a tracer to study the migration of radioactive substances in environmental systems. Tracing the naturally occurring radium isotopes in mineral and water sources allows for the determination of source location, residence time, and concentrations. An understanding of the concentration of radionuclides in our food and water sources is essential to everyone’s health as alpha particle decay is highly damaging in vivo. Due to this high radiobiological effectiveness, there is increased interest in using alpha-emitting radionuclides to prepare new, therapeutic radiopharmaceutical drugs. Selected studies from the recent literature are provided as examples of these modern applications of radium isotopes.

Papain-like cysteine proteases bear an enormous potential as drug discovery targets for both infectious and systemic human diseases. The considerable progress in this field over the last two decades has also raised interest in the visualization of these enzymes in their native context, especially with regard to tumor imaging. After a short introduction to structure and general functions of human cysteine cathepsins, we highlight their importance for drug discovery and development and provide a critical update on the current state of knowledge towards their involvement in tumor progression, with a special emphasis on their role in therapy response. In accordance with a radiopharmaceutical point of view, the main focus of this review article will be the discussion of recently developed fluorescence and radiotracer-based imaging agents together with related molecular probes.

The knowledge of sediment transport in the coastal region is of vital importance to the management of this critical interface between land and sea, where most of the world population lives. For the assessment of sediment behaviour, hydraulic and sediment measurements, bathymetric survey, mathematical and physical models, are applied. Sediment tracers provide a unique capability for understanding sediment transport assisting in sediment management which cannot be obtained any other way, whether conventional monitoring or physical and numerical models because tracers integrate all the hydrodynamic actions in time and space. Computational fluid dynamics (CFD) is now an essential tool for the management of the natural systems and is increasingly used to study the fate and behaviour of particulates and contaminants. Tracer techniques are often employed to validate hydrodynamic models to enhance confidence in the predictive value of the models. In-situ detection afforded by the use of a radioactive tracer allows accurate quantitative determination of the rate of sediment transport, compared with other tracer methods. Also, it is cost effective and safe: its radiological impact to the environment is minimal. Several case studies, performed in different regions of the world, are presented., QC 20150910

A method for synthesis of radiolabelled silver nanoparticles is reported. The method is based on proton activation of silver metal powder, enriched in 107Ag, with a 30.7 MeV proton beam. At this proton energy 105gAg is efficiently created, mainly via the 107Ag(p,3n)105Cd → 105gAg reaction. 105gAg has a half-life of 41.29 days and emits easily detectable gamma radiation on decay to 105Pd. This makes it very useful as a tracing radionuclide for experiments over several weeks or months. Following activation and a period to allow short-lived radionuclides to decay, the powder was dissolved in concentrated nitric acid in order to form silver nitrate (AgNO3), which was used to synthesise radiolabelled silver nanoparticles via the process of sodium borohydride reduction. For comparison, non-radioactive silver nanoparticles were synthesised using commercially supplied AgNO3 in order to check if the use of irradiated Ag powder as a starting material would alter in any way the final nanoparticle characteristics. Both nanoparticle types were characterised using dynamic light scattering, zeta-potential and X-ray diffraction measurements, while additionally the non-radioactive samples were analysed by transmission electron microscopy and UV–Vis spectrometry. A hydrodynamic diameter of about 16 nm was determined for both radiolabelled and non-radioactive nanoparticles, while the electron microscopy on the non-radioactive samples indicated that the physical size of the metal NPs was (7.3 ± 1.4) nm.

Bevacizumab is thought to normalize tumor vasculature and restore the blood-brain barrier, decreasing enhancement and peritumoral edema. Conventional measurements of tumor response rely upon dimensions of enhancing tumor. After bevacizumab treatment, glioblastomas are more prone to progress as nonenhancing tumor. The RANO (Response Assessment in Neuro-Oncology) criteria for glioma response use fluid-attenuated inversion recovery (FLAIR)/T2 hyperintensity as a surrogate for nonenhancing tumor; however, nonenhancing tumor can be difficult to differentiate from other causes of FLAIR/T2 hyperintensity (e.g., radiation-induced gliosis). Due to these difficulties, recent efforts have been directed toward identifying new biomarkers that either predict treatment response or accurately measure response of both enhancing and nonenhancing tumor shortly after treatment initiation. This will allow for earlier treatment decisions, saving patients from the adverse effects of ineffective therapies while allowing them to try alternative therapies sooner. An active area of research is the use of physiologic imaging, which can potentially detect treatment effects before changes in tumor size are evident.

Fatty acid synthase (FASN), the enzyme that synthesizes fatty acid in cells, is over-expressed in prostate cancer and a potential therapeutic target. We have identified several novel chemical scaffolds with potential to inhibit FASN. An extensive series of anti-FASN pharmacophores has been synthesized and characterized for their ability to inhibit recombinant FASN, FASN activity in tumor cells, and to kill prostate cancer cell lines. The best inhibitors have increased potency over other FASN inhibitors, including orlistat, the prototype FASN thioesterase inhibitor. The current studies represent a significant advancement of the development of FASN inhibitors and moves a step closer to translating FASN inhibitors into the clinic., The original document contains color images.

The present work aimed at better understanding metal and metalloid bioaccumulation in the edible Pacific blue shrimp Litopenaeus stylirostris, using both laboratory and field approaches. In the laboratory, the bioaccumulation kinetics of Ag, Cd, Co, Cr, and Zn have been investigated in shrimp exposed via seawater and food, using the corresponding gamma-emitting radiotracers (Ag-110m, Cd-109, Co-57, Cr-51, and Zn-65) and highly sensitive nuclear detection techniques. Results showed that hepatopancreas and intestine concentrated the metals to the highest extent among the blue shrimp organs and tissues. Moulting was found to play a non negligible detoxification role for Co, Cr and, to a lesser extent, Zn. Metal retention by L stylirostris widely varied (from a few days to several months), according to the element and exposure pathway considered (a given metal was usually less strongly retained when ingested with food than when it was taken up from the dissolved phase). In the field study, Ag, As, Cd, Co, Cr, Cu, Mn, Ni, and Zn were analysed in shrimp collected from a New Caledonian aquaculture pond. Metal concentrations in the shrimp muscles were generally relatively low and results confirmed the role played by the digestive organs and tissues in the bioaccumulation/storage/detoxification of metals in the Pacific blue shrimp. Preliminary risk considerations indicate that consumption of the shrimp farmed in New Caledonia is not of particular concern for human health. (C) 2010 Elsevier Ltd. All rights reserved.

The environment is impacted by natural and anthropogenic disturbances that occur at different spatial and temporal scales, and that lead to major changes and even disequilibria when exceeding the resiliency capacities of the ecosystem. With an annual mean flow of 1700 m(3) s(-1), the Rhone River is the largest of the western Mediterranean basin. Its annual solid discharges vary between 2 and 20 Mt, with flood events responsible for more than 70% of these amounts. In the marine coastal area, close to the mouth, both flocculation and aggregation lead to the formation of fine-grained deposits, i.e. the prodelta. This area is characterized by sediment accumulation rates up to 20-50 cm yr(-1) and high accumulations of particle reactive contaminants such as various man-made radionuclides released into the river by nuclear facilities or arising form prior atmospheric nuclear tests (1954-1980) and the Chernobyl accident (April 1986). This prodelta, however, cannot be considered as a permanent repository for particle reactive pollutants since it is subjected to reworking processes. Sediment dynamics had to be linked to the influences of hydrodynamic and atmospheric events such as high flow rates or storms close to the Rhone River mouth. An experiment was carried out during the winter 2006 based on the deployment of two ADCPs and six altimeters at the Grand Rhone mouth for several months. This type of installation has never been used before in this area because of the hard meteorological conditions and the strong fishing activities. However, results showed pluricentimetric rises of the sedimentary level just after river flood events and decreases during storms, generated by southeast winds. Radiotracers and grain size depth profiles helped to characterise the studied events and to establish inventories of sediments and radionuclides. A cruise (CARMEX) was carried out during this same period to collect water samples, suspended particles and sediment cores. The results enabled

Nanotechnology represents a new emerging field in different applications that involves the development, manufacturing of materials in the sub micron range down to the nanometers (nm) range scale. These new materials will soon be able to improve our everyday life and the advantages can be considered enormous and, in the near future, the development of nanotechnologies is expected to have a large socio-economical impact in practically all industrial activity fields. Anyway, the potential risk of these nanomaterials for human health and environment is not clear and remains largely unknown. This work aims to propose, develop and demonstrate the possible use of in vitro methods and systems in order to better understand the toxicology of nanoparticles (NPs) that is a research field in which an integrated approach based on the use of different techniques (e.g. to assess physicochemical characterization of NPs) is required. In particular, four in vitro models were taken into consideration in this study: (i) Balb/3T3 immortalised mouse fibroblasts; (ii) Peripheral Blood Mononuclear Cells (PBMC); (iii) Madin-Darby canine kidney epithelial cells (MDCK cells) and (iv) Human hepatoma cells (HepG2 cells). Considering different in vitro toxicological end-points, the use of in vitro methods was demonstrated to possibly explain some of the effects of Cobalt NPs (Co-nano) and Gold NPs (AuNPs). In particular, standard in vitro tests as well as original newly developed methods were used to assess the cell viability as end point of basal cytotoxicity; morphological transformation for carcinogenic potential; single strand and double strand DNA breaks and chromosomal aberrations for genotoxicity and cellular internalization for biokinetics and NPs intracellular fate. Briefly, the results showed uptake of both NPs; no basal cytotoxicity induced by AuNPs, while cytotoxicity, carcinogenic potential and genotoxicity were demonstrated for Co-nano. Concerning Co-nano, basal cytotoxicity was als, (DOCSC03 ) -- FUNDP, 2009

Uptake of waterborne Cd, Co, Mn and Zn was determined in laboratory experiments using radiotracer techniques (Cd-109, Co-57, Mn-54 and Zn-65). Labelled Zn was mainly accumulated in the digestive gland (65%) and Co in kidneys (81%); Cd and Mn were similarly distributed in digestive gland and gills. In a complementary field study, Ag, As, Cd, Co, Cr, Cu, Fe, Mn, Ni, and Zn were analysed in scallops collected at two stations showing different contamination levels. Digestive gland and kidneys displayed the highest concentrations. Ag, As, Cd, and Fe differed in soft tissues from the two stations, suggesting that Comptopallium radula could be a valuable local biomonitor species for these elements. Low Mn and Zn concentrations found in kidneys suggest that their content in calcium-phosphate concretions differs from the other pectinids. Preliminary risk considerations suggest that As would be the only element potentially leading to exposure of concern for seafood consumers. (c) 2007 Elsevier Ltd. All rights reserved.

Innovation in basic and applied science has brought radiotracers to fruition as diagnostics. Non-invasive, longitudinal, and quantifiable molecular imaging is the key to diagnosing and monitoring numerous illnesses, with more to come from characterization of the clinical relevance of findings from genomics research. Radiotracers enable real-time in vivo studies of the effects of drug candidates on receptors, pathways, pharmacodynamics, and clinically relevant endpoints, thereby providing both early detection of pathophysiology to enable early intervention, and then monitoring of treatment responses to enable individualization of treatment regimens. We review developments which have translated imaging from bench to bedside, or biomarkers to diagnostics. Notable developments include (1) synthesis methods for rapid 11C labeling of biomolecules to high specific radioactivity; (2) ligand-binding assays for screening molecular imaging agents rather than drugs; (3) in vivo imaging of radiotracers in animals; (4) discovering the imaging advantages of 99mTc, 11C, and 18F; (5) co-registration and automated quantitative assessment of high spatial resolution CT and MR images with molecular images from PET for longitudinal studies of treatment effect.

Author Posting. © Elsevier B.V., 2006. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Continental Shelf Research 29 (2006): 1971-1983, doi:10.1016/j.csr.2006.07.011., A field experiment to compare methods of assessing submarine groundwater discharge (SGD) was held on Shelter Island, NY, in May 2002. We evaluated the use of radon, radium isotopes, and methane to assess SGD rates and dynamics from a glacial aquifer in the coastal zone. Fluxes of radon across the sediment-water interface were calculated from changes in measured surface water inventories following evaluation and correction for tidal effects, atmospheric evasion, and mixing with offshore waters. These fluxes were then converted to SGD rates using the measured radon concentration in the groundwater. We used the short-lived radium isotopes to calculate a horizontal mixing coefficient to assess radon loss by mixing between nearshore and offshore waters. We also made an independent calculation of SGD using the Ra-derived mixing coefficient and the long-lived 226Ra concentration gradient in the bay. Seepage rates were calculated to range between 0 and 34 cm.day-1 using the radon measurements and 15 cm.day-1 as indicated by the radium isotopes. The radiotracer results were consistent and comparable to SGD rates measured directly with vented benthic chambers (seepage meters) deployed during this experiment. These meters indicated rates between 2 and 200 cm.day-1 depending on their location. Both the calculated radon fluxes and rates measured directly by the automated seepage meters revealed a clear reproducible pattern of higher fluxes during low tides. Considering that the two techniques are completely independent, the agreement in the SGD dynamics is significant. Methane concentration in groundwater was very low (~30 nM) and not suitable as SGD tracer at this study site., The SGD intercomparison experiment was partially funded by SCOR, LOICZ, and UNESCO (IOC and IHP). W. C. Burnett acknowledges support from CICEET (Grant# 1368-810-41) and ONR (Grant# 1368-769-27). J. P. Chanton acknowledges support from Seagrant (R\C-E-44). The WHOI researchers acknowledge funding from CICEET (#NA07OR0351, NA17OZ2507).

The goal of this research project is to develop radiotracers for imaging the proliferative status of breast tumors using the noninvasive imaging technique, Positron Emission Tomography (PET). The strategy taken involves developing radiotracers having a high affinity and selectivity for the sigma (sub 2) receptor, which has been shown to be a useful receptor-based biomarker of proliferation in breast tumor cells growing both in vitro and in vivo. During the second year of the three-year IDEA project, we identified a new class of ligands displaying an outstanding affinity and selectivity for sigma (sub 2) versus sigma (sub 1) receptors. Preliminary in vivo biodistribution and microPET imaging studies with Br-76, C-11 and I-125-labeled analogs indicate that these agents may be useful for use in the diagnosis and determination of the proliferative status of breast tumors in breast cancer patients., The original document contains color images.

WKNI completed a Cooperative Agreement with AFRL to attempt to develop an infrastructure and demonstration project to exhibit and utilize technological developments with applications potentially valuable to both a military and civilian mission. Integrating mission critical information from a variety of formats and sources, and making them available to a highly trained operator, were seen as parallels between Air Force pilot and flight crew needs and the needs of a neurosurgeon and surgery team. Using the specialized knowledge and experience of the Human Effectiveness Directorate, we attempted to apply this knowledge to a civilian environment in the application and development of this technology., The original document contains color images.

This report summarizes the work completed in Year 2 of this grant. The work included continuing to optimize the geometry of the system configuration, emulating the system point spread function, developing an algorithm to generate three-dimensional reconstructions, collecting projection data for the small and large cameras, and generating three-dimensional reconstructions of the radiotracer distribution within the breast phantom The work was significantly hampered by the catastrophic failure of an essential computer system. A significant amount of time and energy was consumed in the efforts to fully recover from the failure, and, as a result, the principal investigator was not able to complete several of the tasks specified in Year 2 of the grant. Work on these unfinished tasks will continue into Year 3, but modifications to the Statement of Work will most likely be required. The parallel-hole collimator for the small camera was selected and installed. Projection data of the large breast phantom was collected for the small camera. Projection data of the large breast phantom was emulated for the proposed large camera by combining several shifted but overlapping projections collected with the small camera.

The diagnosis and staging of breast cancer could be improved by the development of imaging radiopharmaceuticals that provide a non-invasive determination of the estrogen receptor (ER) status of tumor cells. Towards this goal, we have synthesized a number of Re and Tc-labeled estradiol (1) mimics based on the conjugated design, which tethers a metal-containing moiety to an existing steroid. In this study, the 7alpha position of estradiol was chosen as the tether site, due to its well known tolerance of bulky substituents. 1 The metal was stabilized using either the "3+1" design (2,3), or the cyclopentadienyltricarbonylmetal (CpTM) approach (4,5,6) . In the "3+1" design, a tridentate ligand and a monodentate ligand surround an oxometal core.2 In the CpTM design, a substituted Cp and three carbonyls are coordinated to a Re/Tc(I) center.3,4 The advantages of using the "3+1" and CpTM desings are the well-established stability of both systems, as well as the ability to produce both systems efficiently at the tracer level.2,4 The first tether used was a hexyl spacer, and the synthesis of the precursors for targets 2-6 started with THP-protected estradiol 7 (Scheme 1). After oxidation to ketone 8 using a previously published method,

This report summarizes the work completed in Year 1 of this grant. The work included characterizing radioactivity within the breast building phantoms for imaging modeling the detector response and optimizing the imaging system geometry. Standard clinical injections of Tc-99m Sestamibi contain 20 mCi of activity. The estimated percentage of the activity taken up by a single breast of average mass is about 0.08 %, which corresponds to about 16 uCi. The estimated activity per unit mass of normal breast tissue is 43 dpm/mg. The uptake of Tc-99m Sestamibi in abnormal breast tissues (relative to normal tissue) was examined. The degree of uptake varied significantly with the histological type (not grade) of malignant tumors. The mean responses of the small and large modular cameras were characterized. An optical model providing estimates of the camera response to gamma rays incident anywhere on the camera face, was developed.

The dosimetry of new positron emitting radiopharmaceuticals is initially estimated using animal tissue and organ biodistributions assessed invitro. Such methods are time and labor intensive and can have limited accuracy. This research investigated two alternative methods by which biodistribution can be obtained from the laboratory rat: invitro organ measurements using a reduced sacrifice technique, and invivo measurements using single photon emission computed tomography (SPECT). As an alternative to a four time-point sacrifice method, a two time-point method was evaluated as a means to determine the organ cumulated activity of C labeled radiopharmaceuticals. Residence times calculated using two time-points acquired during the first half-life of C were either equivalent or larger than those resulting from using four sacrifice times. Correction factors were required for the urinary bladder and gallbladder when using this simplified technique due to delayed uptakes. Invivo assessments were performed with SPRINT, a full ring detector SPECT system using a slit aperture to obtain a 3-to-1 object to image magnification ratio. Acceptable resolution for 511 keV photons was achieved using a high energy parallel slice collimator and a novel technique to correct for penetration of the slit aperture by high energy photons. The resulting system resolution was approximately 4.5 mm axially and transaxially. System sensitivity was approx. 55 cpm/micronCi, a consequence of high resolution collimation and poor intrinsic detector efficiency.

This project has as its objective the development of radiotracer imaging technology to follow the in vivo circulation and organ deposition of liposome encapsulated hemoglobin (LEH). LEH will be labeled with technetium-99m (99m Tc) or indium-111 (111In) and infused into small animals to monitor any in vivo differences between different LEH formulations. These studies will be correlated with any hematological and pathological changes associated with LEH treatment. Development of such non-invasive monitoring techniques may lead to significant cost effective manufacturing and formulation improvements, and ultimately a more efficacious LEH product. The development of this elegant labeling technique should make it possible to study the effect of various LEH modifications on biodistribution non-invasively in primates and humans.

This project has as its objective the development of radiotracer imaging technology to follow the in vivo circulation and organ deposition of liposome encapsulated hemoglobin (LEH). LEH will be labeled with technetium-99m or indium-111 and infused into small animals to monitor any in vivo differences between different LEH formulations. These studies will be correlated with any hematological and pathological changes associated with LEH treatment. Development of such non-invasive monitoring techniques may lead to significant cost effective manufacturing and formulation improvements, and ultimately a more efficacious LEH product. The development of this elegant labeling technique should make it possible to study the effect of various LEH modifications on biodistribution non-invasively in primates and humans.