Improved synthesis of SV2A targeting radiotracer [11C]UCB-J

Abstract Introduction [11C]UCB-J is a tracer developed for PET (positron emission tomography) that has high affinity towards synaptic vesicle glycoprotein 2A (SV2A), a protein believed to participate in the regulation of neurotransmitter release in neurons and endocrine cells. The localisation of SV2A in the synaptic terminals makes it a viable target for in vivo imaging of synaptic density in the brain. Several SV2A targeting compounds have been evaluated as PET tracers, including [11C]UCB-J, with the aim to facilitate studies of synaptic density in neurological diseases. The original two-step synthesis method failed in our hands to produce sufficient amounts of [11C]UCB-J, but served as an excellent starting point for further optimizations towards a high yielding and simplified one-step method. [11C]Methyl iodide was trapped in a clear THF-water solution containing the trifluoroborate substituted precursor, potassium carbonate and palladium complex. The resulting reaction mixture was heated at 70 °C for 4 min to produce [11C]UCB-J. Results After semi-preparative HPLC purification and reformulation in 10% ethanol/phosphate buffered saline, the product was obtained in 39 ± 5% radiochemical yield based on [11C]methyl iodide, corresponding to 1.8 ± 0.5 GBq at EOS. The radiochemical purity was > 99% and the molar activity was 390 ± 180 GBq/μmol at EOS. The product solution contained < 2 ppb palladium. Conclusions A robust and high yielding production method has been developed for [11C]UCB-J, suitable for both preclinical and clinical PET applications.

Download Full-text

Anticancer Activity of Zinc Nanoparticles Made using Terpenoids from Aqueous Leaf Extract of Andrographis Paniculata

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2015.8.4.4 ◽

2015 ◽

Vol 8 (4) ◽

pp. 3018-3023

Author(s):

M Dhamodaran ◽

S Kavitha

Keyword(s):

Green Synthesis ◽

Metal Nanoparticles ◽

Cancer Cells ◽

Synthesis Method ◽

Pollution Prevention ◽

Andrographis Paniculata ◽

Assay Method ◽

Synthesis Process ◽

Excellent Starting Point ◽

Starting Point

In recent years, the evolution of green chemistry in the production of nanoparticles has wrapped up an immense consideration because traces of chemicals left unreacted in the chemical synthesis process can be precarious. Green synthesis of metal nanoparticles is an interesting issue of the nanoscience and nanobiotechnology. There is a growing attention to biosynthesis the metal nanoparticles using organisms. Among these organisms, plants seem to be the best candidate and they are suitable for large scale biosynthesis of nanoparticles. Nanoparticles produced by plants are more stable, and the rate of synthesis is faster than that in the case of other organisms. Natural products, especially of plant origin, represent an excellent starting point for research. In traditional medicine there are also several plants that are used to treat many diseases. Therefore, a competent protocol for the production of Zn- NPs without calcinations was developed by green synthesis method using one of the major constituents, terpenoids from aqueous leaf extracts of Andrographis paniculata. Among the single compounds extracted from Andrographis paniculata, andrographolide is the major one in terms of bioactive properties and abundance. The anticancer activities of Zn-TAP NPs have been evaluated in cancer models such as HeLa, Hep-2 cells and were examined in different concentrations by MTT assay method. The Zn-TAP NPs showed a maximum activity against HeLa (human cervical cancer cells) and Hep-2 (human liver cancer cells) with maximal inhibition of 59% and 63% at 250 µg/ml, respectively. This approach offers environmentally beneficial alternatives to more hazardous chemicals and processes and promotes pollution prevention by the production of nanoparticle in their natural environs.

Download Full-text

Automatic Production and Preliminary PET Imaging of a New Imaging Agent [18F]AlF-FAPT

Frontiers in Oncology ◽

10.3389/fonc.2021.802676 ◽

2022 ◽

Vol 11 ◽

Author(s):

JiaWen Huang ◽

LiLan Fu ◽

KongZhen Hu ◽

Shun Huang ◽

YanJiang Han ◽

...

Keyword(s):

Pet Imaging ◽

Tumor Imaging ◽

Solid Phase ◽

Synthesis Method ◽

Imaging Agent ◽

Step Method ◽

Abdominal Tumor ◽

Automatic Production ◽

Biodistribution Studies

BackgroundFibroblast activating protein (FAP) has become an important target for cancer diagnostic imaging and targeted radiotherapy. In particular, [18F]FAPI-42 has been successfully applied to positron emission tomography (PET) imaging of various tumors. However, it exhibits high hepatobiliary metabolism and is thus not conducive to abdominal tumor imaging. This study reports a novel 18F-labeled FAP inhibitor, [18F]AlF-FAPT, a better FAPI imaging agent than [18F]FAPI-42.Materials and MethodsThe precursor of [18F]AlF-FAPT (NOTA-FAPT) was designed and synthesized using the standard FMOC solid phase synthesis method. [18F]AlF-FAPT was subsequently synthesized and radiolabeled with 18F using the AllInOne synthesis module. Dynamic MicroPET and biodistribution studies of [18F]AlF-FAPT were then conducted in xenograft tumor mouse models to determine its suitability.ResultsThe precursors NOTA-FAPT were obtained with a chemical purity of > 95%. [18F]AlF-FAPT was synthesized automatically using the cassette-based module AllInOne within 40 min. The non-decay corrected radiochemical yield was 25.0 ± 5.3% (n=3). In vivo imaging and biodistribution studies further demonstrated that compared with [18F]-FAPI-42, [18F]AlF-FAPT had a lower hepatobiliary uptake than [18F]FAPI-42, which was advantageous for imaging abdominal tumors.Conclusion[18F]AlF-FAPT can be synthesized automatically using a one-step method of aluminum fluoride. Collectively, [18F]AlF-FAPT is a better FAPI imaging agent than [18F]FAPI-42. This study proves the feasibility of using [18F]AlF-FAPT as a new radioactive tracer for PET imaging.

Download Full-text

Click Chemistry Expedited Radiosynthesis: Sulfur [18F]fluoride Exchange of Aryl Fluorosulfates

10.26434/chemrxiv.10314647.v1 ◽

2019 ◽

Cited By ~ 1

Author(s):

Qinheng Zheng ◽

Hongtao Xu ◽

Hua Wang ◽

Wen-Ge Han Du ◽

Nan Wang ◽

...

Keyword(s):

Click Chemistry ◽

High Performance ◽

Isotopic Exchange ◽

Tumor Imaging ◽

Radiochemical Yield ◽

Exchange Method ◽

Molar Activity ◽

Positron Emission ◽

Sulfur Fluoride

The lack of simple, efficient [18F]fluorination processes and new target-specific organofluorine probes remains the major challenge of fluorine-18-based positron emission tomography (PET). We report here a fast isotopic exchange method for the radiosynthesis of aryl [18F]fluorosulfate based PET agents enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully-automated 18F-radiolabeling of twenty-five structurally diverse aryl fluorosulfates with excellent radiochemical yield (83–100%) and high molar activity (up to 281 GBq µmol–1) at room temperature in 30 seconds. The purification of radiotracers requires no time-consuming high-performance liquid chromatography (HPLC), but rather a simple cartridge filtration. The utility of aryl [18F]fluorosulfate is demonstrated by the in vivo tumor imaging by targeting poly(ADP-ribose) polymerase 1 (PARP1).

Download Full-text

68Ga-labeled HBED-CC Variant of uPAR Targeting Peptide AE105 Compared with 68Ga-NODAGA-AE105

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180316152618 ◽

2019 ◽

Vol 18 (9) ◽

pp. 1289-1294 ◽

Cited By ~ 1

Author(s):

Kusum Vats ◽

Rohit Sharma ◽

Haladhar D. Sarma ◽

Drishty Satpati ◽

Ashutosh Dash

Keyword(s):

Solid Phase ◽

Evaluation Studies ◽

Radiochemical Yield ◽

In Vivo Evaluation ◽

Peptide Conjugates ◽

Biodistribution Studies ◽

Target Organs ◽

U87mg Tumor

Aims: The urokinase Plasminogen Activator Receptors (uPAR) over-expressed on tumor cells and their invasive microenvironment are clinically significant molecular targets for cancer research. uPARexpressing cancerous lesions can be suitably identified and their progression can be monitored with radiolabeled uPAR targeted imaging probes. Hence this study aimed at preparing and evaluating two 68Ga-labeled AE105 peptide conjugates, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 as uPAR PET-probes. Method: The peptide conjugates, HBED-CC-AE105-NH2 and NODAGA-AE105-NH2 were manually synthesized by standard Fmoc solid phase strategy and subsequently radiolabeled with 68Ga eluted from a commercial 68Ge/68Ga generator. In vitro cell studies for the two radiotracers were performed with uPAR positive U87MG cells. Biodistribution studies were carried out in mouse xenografts with the subcutaneously induced U87MG tumor. Results: The two radiotracers, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 that were prepared in >95% radiochemical yield and >96% radiochemical purity, exhibited excellent in vitro stability. In vivo evaluation studies revealed higher uptake of 68Ga-HBED-CC-AE105 in U87MG tumor as compared to 68Ga-NODAGAAE105; however, increased lipophilicity of 68Ga-HBED-CC-AE105 resulted in slower clearance from blood and other non-target organs. The uPAR specificity of the two radiotracers was ascertained by significant (p<0.05) reduction in the tumor uptake with a co-injected blocking dose of unlabeled AE-105 peptide. Conclusion: Amongst the two radiotracers studied, the neutral 68Ga-NODAGA-AE105 with more hydrophilic chelator exhibited faster clearance from non-target organs. The conjugation of HBED-CC chelator (less hydrophilic) resulted in negatively charged 68Ga-HBED-CC-AE105 which was observed to have high retention in blood that decreased target to non-target ratios.

Download Full-text

Improved in vivo PET imaging of the adenosine A2A receptor in the brain using [18F]FLUDA, a deuterated radiotracer with high metabolic stability

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-020-05164-4 ◽

2021 ◽

Author(s):

Thu Hang Lai ◽

Magali Toussaint ◽

Rodrigo Teodoro ◽

Sladjana Dukić-Stefanović ◽

Daniel Gündel ◽

...

Keyword(s):

Specific Binding ◽

Radiochemical Yield ◽

Toxicity Study ◽

In Vivo Evaluation ◽

One Pot ◽

Specific Binding Ratio ◽

Mri Studies ◽

The Brain

Abstract Purpose The adenosine A2A receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A2A receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A2A receptor radiotracer and report herein the preclinical evaluation of [18F]FLUDA, a deuterated isotopologue of [18F]FESCH. Methods [18F]FLUDA was synthesized by a two-step one-pot approach and evaluated in vitro by autoradiographic studies as well as in vivo by metabolism and dynamic PET/MRI studies in mice and piglets under baseline and blocking conditions. A single-dose toxicity study was performed in rats. Results [18F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72–180 GBq/μmol. Autoradiography proved A2A receptor–specific accumulation of [18F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [18F]FLUDA compared to that of [18F]FESCH, resulting in the absence of brain-penetrant radiometabolites. Furthermore, the radiometabolites detected in piglets are expected to have a low tendency for brain penetration. PET/MRI studies confirmed high specific binding of [18F]FLUDA towards striatal A2A receptor with a maximum specific-to-non-specific binding ratio in mice of 8.3. The toxicity study revealed no adverse effects of FLUDA up to 30 μg/kg, ~ 4000-fold the dose applied in human PET studies using [18F]FLUDA. Conclusions The new radiotracer [18F]FLUDA is suitable to detect the availability of the A2A receptor in the brain with high target specificity. It is regarded ready for human application.

Download Full-text

Globalization Impact on Multinational Enterprises

World ◽

10.3390/world2020014 ◽

2021 ◽

Vol 2 (2) ◽

pp. 216-230

Author(s):

Justine Kyove ◽

Katerina Streltsova ◽

Ufuoma Odibo ◽

Giuseppe T. Cirella

Keyword(s):

Developing Country ◽

Multinational Enterprises ◽

Developed Countries ◽

Global Market ◽

Data Availability ◽

Negative Effects ◽

Developed Country ◽

Excellent Starting Point ◽

Starting Point ◽

The Impact

The impact of globalization on multinational enterprises was examined from the years 1980 to 2020. A scoping literature review was conducted for a total of 141 articles. Qualitative, quantitative, and mixed typologies were categorized and conclusions were drawn regarding the influence and performance (i.e., positive or negative effects) of globalization. Developed countries show more saturated markets than developing countries that favor developing country multinational enterprises to rely heavily on foreign sales for revenue growth. Developed country multinationals are likely to use more advanced factors of production to create revenue, whereas developing country multinationals are more likely to use less advanced forms. A number of common trends and issues showed corporate social responsibility, emerging markets, political issues, and economic matters as key to global market production. Recommendations signal a strong need for more research that addresses contributive effects in the different economies, starting with the emerging to the developed. Limitations of data availability and inconsistency posed a challenge for this review, yet the use of operationalization, techniques, and analyses from the business literature enabled this study to be an excellent starting point for additional work in the field.

Download Full-text

Silica Monolith for the Removal of Pollutants from Gas and Aqueous Phases

Molecules ◽

10.3390/molecules26051316 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1316

Author(s):

Vanessa Miglio ◽

Chiara Zaccone ◽

Chiara Vittoni ◽

Ilaria Braschi ◽

Enrico Buscaroli ◽

...

Keyword(s):

Rhodamine B ◽

Water Solution ◽

Synthesis Method ◽

Textural Properties ◽

Adsorption Properties ◽

Water Soluble ◽

Silica Monoliths ◽

Physico Chemical ◽

Gaseous Toluene ◽

Mcm 41

This study focused on the application of mesoporous silica monoliths for the removal of organic pollutants. The physico-chemical textural and surface properties of the monoliths were investigated. The homogeneity of the textural properties along the entire length of the monoliths was assessed, as well as the reproducibility of the synthesis method. The adsorption properties of the monoliths for gaseous toluene, as a model of Volatile Organic Compounds (VOCs), were evaluated and compared to those of a reference meso-structured silica powder (MCM-41) of commercial origin. Silica monoliths adsorbed comparable amounts of toluene with respect to MCM-41, with better performances at low pressure. Finally, considering their potential application in water phase, the adsorption properties of monoliths toward Rhodamine B, selected as a model molecule of water soluble pollutants, were studied together with their stability in water. After 24 h of contact, the silica monoliths were able to adsorb up to the 70% of 1.5 × 10−2 mM Rhodamine B in water solution.

Download Full-text

Delivering and implementing child and adolescent mental health training for mental health and allied professionals: a systematic review and qualitative meta-aggregation

BMC Medical Education ◽

10.1186/s12909-021-02530-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Emily Banwell ◽

Neil Humphrey ◽

Pamela Qualter

Keyword(s):

Mental Health ◽

Systematic Review ◽

Qualitative Research ◽

Mental Health Professionals ◽

Synthesis Method ◽

Barriers And Facilitators ◽

Youth Workers ◽

Mental Health Training ◽

Health Training ◽

Starting Point

Abstract Background The increasing prevalence of mental health difficulties among children and young people (CYP) suggests that early intervention is vital. A comprehensive system of care and support requires the involvement of mental health professionals, including psychologists and psychiatrists, and allied professionals, including teachers, police, and youth workers. A critical starting point is the provision of effective training, in order that these professionals can better support the mental health needs of the CYP that they encounter. Objectives Given the primacy of training in the CYP mental health support system, understanding the factors that maximise potential gains and facilitate uptake is pertinent. The current review therefore located and explored qualitative research evidence, to identify the barriers and facilitators underpinning successful delivery and implementation of training focussed on the mental health of CYP, for both mental health and allied professionals. Methods A systematic review and qualitative meta-aggregation were conducted. Systematic searches were carried out using ASSIA, EMBASE, MEDLINE, NICE Evidence, PsycINFO, and Scopus databases, for papers published between 2000 and 2020. Twelve thousand four hundred forty-eight records were identified, of which 39 were eligible for review. The records were appraised for quality using the Joanna Briggs Institute Critical Appraisal Checklist for Qualitative Research, and synthesised using the qualitative meta-aggregation method. Results One hundred eighty-two raw findings were extracted from the 39 papers, which were condensed into 47 sub-categories, 19 categories, and finally 5 synthesis statements. These synthesis statements reflected the barriers and facilitators influencing the training delivery process (“support”; “content, design, and planning”), and the implementation of training into the workplace (“context”; “perceived value”; “organisational factors”). Conclusions The synthesis statements and underlying categories provide practical recommendations for those designing, delivering, or implementing CYP mental health training. Recommendations ranged from facilitating peer support during training, to the idea that training will be better implemented when perceived need is high. The review provides a robust evidence-based foundation to “common-sense” principles, drawing them into a coherent and organised framework using a synthesis method grounded in pragmatism. Protocol registration number PROSPERO reference ID: CRD42020162876.

Download Full-text

In vivo synaptic density relates to glucose metabolism at rest in healthy subjects, but is strongly modulated by regional differences

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20981502 ◽

2021 ◽

pp. 0271678X2098150

Author(s):

June van Aalst ◽

Jenny Ceccarini ◽

Stefan Sunaert ◽

Patrick Dupont ◽

Michel Koole ◽

...

Keyword(s):

Glucose Metabolism ◽

Medial Temporal Lobe ◽

Regional Differences ◽

Specific Binding ◽

Aerobic Glycolysis ◽

Glucose Consumption ◽

Brain Regions ◽

Synaptic Density ◽

Energy Demands

Preclinical and postmortem studies have suggested that regional synaptic density and glucose consumption (CMRGlc) are strongly related. However, the relation between synaptic density and cerebral glucose metabolism in the human brain has not directly been assessed in vivo. Using [11C]UCB-J binding to synaptic vesicle glycoprotein 2 A (SV2A) as indicator for synaptic density and [18F]FDG for measuring cerebral glucose consumption, we studied twenty healthy female subjects (age 29.6 ± 9.9 yrs) who underwent a single-day dual-tracer protocol (GE Signa PET-MR). Global measures of absolute and relative CMRGlc and specific binding of [11C]UCB-J were indeed highly significantly correlated ( r > 0.47, p < 0.001). However, regional differences in relative [18F]FDG and [11C]UCB-J uptake were observed, with up to 19% higher [11C]UCB-J uptake in the medial temporal lobe (MTL) and up to 17% higher glucose metabolism in frontal and motor-related areas and thalamus. This pattern has a considerable overlap with the brain regions showing different levels of aerobic glycolysis. Regionally varying energy demands of inhibitory and excitatory synapses at rest may also contribute to this difference. Being unaffected by astroglial and/or microglial energy demands, changes in synaptic density in the MTL may therefore be more sensitive to early detection of pathological conditions compared to changes in glucose metabolism.

Download Full-text

Non-Isothermal Decomposition as Efficient and Simple Synthesis Method of NiO/C Nanoparticles for Asymmetric Supercapacitors

Nanomaterials ◽

10.3390/nano11010187 ◽

2021 ◽

Vol 11 (1) ◽

pp. 187

Author(s):

Daria Chernysheva ◽

Ludmila Pudova ◽

Yuri Popov ◽

Nina Smirnova ◽

Olga Maslova ◽

...

Keyword(s):

Nickel Oxide ◽

Synthesis Method ◽

Average Diameter ◽

Carbon Support ◽

Spherical Particles ◽

Support Surface ◽

Isothermal Decomposition ◽

Step Method ◽

Nickel Oxide Nanoparticles ◽

Electrode Cell

A series of NiO/C nanocomposites with NiO concentrations ranging from 10 to 90 wt% was synthesized using a simple and efficient two-step method based on non-isothermal decomposition of Nickel(II) bis(acetylacetonate). X-ray diffraction (XRD) measurements of these NiO/C nanocomposites demonstrate the presence of β-NiO. NiO/C nanocomposites are composed of spherical particles distributed over the carbon support surface. The average diameter of nickel oxide spheres increases with the NiO content and are estimated as 36, 50 and 205 nm for nanocomposites with 10, 50 and 80 wt% NiO concentrations, respectively. In turn, each NiO sphere contains several nickel oxide nanoparticles, whose average sizes are 7–8 nm. According to the tests performed using a three-electrode cell, specific capacitance (SC) of NiO/C nanocomposites increases from 200 to 400 F/g as the NiO content achieves a maximum of 60 wt% concentration, after which the SC decreases. The study of the NiO/C composite showing the highest SC in three- and two-electrode cells reveals that its SC remains almost unchanged while increasing the current density, and the sample demonstrates excellent cycling stability properties. Finally, NiO/C (60% NiO) composites are shown to be promising materials for charging quartz clocks with a power rating of 1.5 V (30 min).

Download Full-text