Validation of two fluoro-analogues of N,N-dimethyl-2-(2′-amino-4′-hydroxymethyl-phenylthio)benzylamine as serotonin transporter imaging agents using microPET

IntroductionCarbon-11 (C-11) N,N-dimethyl-2-(2′-amino-4′-hydroxymethyl-phenylthio)benzylamine ([¹¹C]HOMADAM) has been reported as highly specific and selective positron emission tomography (PET) radiotracer showing fast kinetics for the human brain serotonin transporter (SERT). In our continued effort to develop appropriate PET SERT radioligand that can be labeled with either C-11 or fluorine-18 (F-18), two new C-11 labeled analogues of HOMADAM, [¹¹C]-N,N-dimethyl-2-(2′-amino-5′-fluoro-4′-hydroxymethyl-phenylthio)benzylamine ([¹¹C]-(2)) and [¹¹C]-N,N-dimethyl-2-(2′-amino-4-fluoro-4′-hydroxymethyl-phenylthio)benzylamine ([¹¹C]-(3)) have been synthesized and evaluated along the previously reported [¹¹C]-N,N-dimethyl-2-(2′-amino-5-fluoro-4′-hydroxymethyl-phenylthio)benzylamine ([¹¹C]-(1)).MethodsThe in vitro competitive binding assays were performed in cells transfected with human SERT (hSERT), human dopamine transporter (hDAT), and human norepinephrine transporter (hNET). [¹¹C]-(2) and [¹¹C]-(3) were prepared by methylation of their monomethylbenzylamine precursors 13 and 22 with cyclotron produced [¹¹C]iodomethane ([¹¹C]CH₃I), respectively. Uptake and kinetics of [¹¹C]-(2) and [¹¹C]-(3) in the brain regions of interest were determined in anesthetized rhesus monkeys using Concorde microPET P4.Results2 and 3 displayed moderate and high affinity for the SERT with Kis (SERT) = 5.45 and 1.10 nM (vs [³H]citalopram), respectively. After High Performance Liquid Chromatography (HPLC) purification, [¹¹C]-(2) and [¹¹C]-(3) were obtained in 23 and 9% radiochemical yield (RCY) and log Ps_7.4 of 1.77 and 1.91, respectively. The microPET images of [¹¹C]-(2) and [¹¹C]-(3) showed clear localization in the monkey brain regions rich in SERT with midbrain to cerebellum ratios of 1.75 and 3.86 at 85 min post injection, respectively, comparing to 3.40 for [¹¹C]-(1), at the same time. [¹¹C]-(3) was selected for further examination and showed to be specific to the SERT as displacement with citalopram (a potent SERT ligand) reduced radioactivity in SERT rich regions, such as midbrain, to the cerebellum level.ConclusionsCompound 2, the 5′-fluoro-analogue of HOMADAM, had the lowest brain uptake and target to non-target ratios. Compound 3, the 4-fluoro-analogue of HOMADAM, had good brain uptake and higher midbrain and thalamus to cerebellum ratios than compound 1, the 5-fluoro-analogue of HOMADAM. Although 1 and 3 presented better imaging properties than 2, none of the three candidates was suitable to surpass the binding or distributional qualities of the parent HOMADAM. Alternative fluoro-analogues of HOMADAM will soon be characterized, in future work, as SERT radioimaging agents.     

Bone marrow mesenchymal stem cells suppress IL-9 in adjuvant-induced arthritis

Interleukin-9 (IL-9) has been shown to be upregulated in rheumatoid arthritis (RA). The exact role of IL-9 has not yet been effectively studied. Mesenchymal stem cells (MSCs) have shown a promising immunomodulatory role towards repairing cartilage and restoring joint function. One of the key problems influencing the therapeutic efficacy of stem cell therapy is the poor cell survival following transplantation. This is attributed to oxidative and inflammatory stresses at the injured sites. Hesperidin (Hsd), a flavanone present in citrus fruits, has been studied as potential therapeutic agents that have anti-oxidant and anti-inflammatory activities. The objective of this study is to evaluate the therapeutic paracrine action of bone marrow MSCs on the IL-9 level in adjuvant-induced arthritis (AIA) and the enhancement effect of Hsd on transplanted MSCs. Articular tissue inflammation and cartilage damage were assessed by histological scoring. Antinuclear autoantibodies, tumour necrosis factor-alpha (TNF-α), IL-9, IL-4, interferon gamma (IFN-δ), and transforming growth factor-beta1 (TGF-β1), as well as malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) levels, were assessed in spleen tissue homogenates after treatment with MSCs either alone or combined with Hsd for 4 weeks in an AIA rat model. Results of this study confirmed that MSCs decreased IL-9 levels in AIA and provide novel insights into the application of Hsd on MSC-based treatments.

• Highlights

• Adjuvant-induced arthritis (AIA) is one of the most widely used models that has a great similarity to rheumatoid arthritis (RA).

• Few studies in recent years have estimated IL-9 in rheumatic diseases and it remains an understudied cytokine.

• For the first time, bone marrow mesenchymal stem cells (MSCs) therapy has a vital role in splenocytes IL-9 level and further studies are required.

• Combined therapy of MSCs with antioxidants as hesperidin (Hsd) can alleviate oxidative stress and enhance stem cells immunomodulatory action.

     

Carriers for the targeted delivery of aerosolized macromolecules for pulmonary pathologies

Introduction: Macromolecules with unique effects and potency are increasingly being considered for application in lung pathologies. Numerous delivery strategies for these macromolecules through the lung have been investigated to improve the targeting and overall efficacy.

Areas covered: Targeting approaches from delivery devices, formulation strategies and specific targets are discussed.

Expert opinion: Although macromolecules are a heterogeneous group of molecules, a number of strategies have been investigated at the macro, micro, and nanoscopic scale for the delivery of macromolecules to specific sites and cells of lung tissues. Targeted approaches are already in use at the macroscopic scale through inhalation devices and formulations, but targeting strategies at the micro and nanoscopic scale are still in the laboratory stage. The combination of controlling lung deposition and targeting after deposition, through a combination of targeting strategies could be the future direction for the treatment of lung pathologies through the pulmonary route.     

The metabolomic analysis of five Mentha species: cytotoxicity,anti-Helicobacter assessment,and the development of polymeric micelles for enhancing the anti-Helicobacter activity

Mentha species are medicinally used worldwide and remain attractive for research due to the diversity of their phytoconstituents and large therapeutic indices for various ailments. This study used the metabolomics examination of five Mentha species (M. suaveolens, M. sylvestris, M. piperita, M. longifolia, and M. viridis) to justify their cytotoxicity and their anti-Helicobacter effects. The activities of species were correlated with their phytochemical profiles by orthogonal partial least square discriminant analysis (OPLS-DA). Tentatively characterized phytoconstituents using liquid chromatography high-resolution electrospray ionization mass spectrometry (LC-HR-ESI-MS) included 49 compounds: 14 flavonoids, 10 caffeic acid esters, 7 phenolic acids, and other constituents. M. piperita showed the highest cytotoxicity to HepG2 (human hepatoma), MCF-7 (human breast adenocarcinoma), and CACO2 (human colon adenocarcinoma) cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. OPLS-DA and dereplication studies predicted that the cytotoxic activity was related to benzyl glucopyranoside-sulfate, a lignin glycoside. Furthermore, M. viridis was effective in suppressing the growth of Helicobacter pylori at a concentration of 50 mg mL⁻¹. OPLS-DA predicted that this activity was related to a dihydroxytrimethoxyflavone. M. viridis extract was formulated with Pluronic® F127 to develop polymeric micelles as a nanocarrier that enhanced the anti-Helicobacter activity of the extract and provided minimum inhibitory concentrations and minimum bactericidal concentrations of 6.5 and 50 mg mL⁻¹, respectively. This activity was also correlated to tentatively identified constituents, including rosmarinic acid, catechins, carvone, and piperitone oxide.

Mentha species are medicinally used worldwide and remain attractive for research due to the diversity of their phytoconstituents and large therapeutic indices for various ailments.     

Prevalence and determinants of distress among oncology patients at a tertiary care medical city in Riyadh,Saudi Arabia

Objectives:To estimate the prevalence of distress in patients with cancer in Saudi Arabia and to identify common psychosocial stressors in these patients. We also looked for associations between distress and psychological, sociodemographic, and medical factors.Methods:This cross-sectional study was performed in the oncology outpatient clinic at King Saud University Medical City, Riyadh, Saudi Arabia, from January 2018 to December 2019. It included 280 patients with breast cancer, colorectal cancer, or lymphoma. Sociodemographic information was collected using questionnaire, along with information on medical history and any psychiatric history. Distress was assessed using the Distress Thermometer and Problem List. Satisfaction with social support was rated using the visual analog scale. All patients were screened for depression using the Patient Health Questionnaire 9-item depression scale and anxiety using the Generalized Anxiety Disorder 7-item scale.Results:The prevalence of distress in our study population was found to be 46%. Distress was associated with several practical, family, emotional, and physical stressors in the problem list. Logistic regression identified predictors of distress to be anxiety (odds ratio [OR] 8.7, confidence interval [CI] 1.98-38.24, p=0.002) and receiving radiotherapy (OR 3.6, CI 1.33-9.99, p=0.009), while Saudi nationality (OR 0.22, CI 0.05-0.95, p=0.037) and stage I cancer (OR 0.18, CI 0.05-1.40, p=0.002) were associated with low distress.Conclusion:Approximately half of cancer patients were found to have distress. Anxiety, advanced cancer stage, and radiotherapy were independently associated with distress.     

Radiologic technologists in Saudi Arabia: Does long-term exposure to radiation increase the risk of hematological disorders?

Objectives:To determine the influence of prolonged exposure to radiation based on dosimeter readings on hematological parameters among radiologic technologists (RTs) in Saudi Arabia.Methods:The study was specifically conducted on selected RTs with experience of more than 10 years and the highest thermoluminescent dosimeter (TLD) readings among all RTs in the Radiological Department, Sabya General Hospital, Ministry of Health, Saudi Arabia from August to October 2020. The RTs group was compared with a control group of non-irradiated participants. Blood samples were collected for hematological and coagulation profile evaluation.Results:The acquired radiation dose analysis revealed that the average accumulated dose in 10 years is 7.6 mSv. The medians of prothrombin time (PT) and activated partial thromboplastin time (APTT) of the RTs group were significantly lower when compared to the control group. In addition, RTs group exhibited a significant reduction in neutrophil count and an elevation in lymphocyte count.Conclusion:Chronic exposure to radiation revealed a significant change in blood tests and may reflect an effect on RTs tissues, leading to serious health problems. However, further investigation in a large cohort to study the association between alteration in hematological parameters and chronic radiation exposure is required.     

Synthesis of Novel Nano-Sulfonamide Metal-Based Corrosion Inhibitor Surfactants

The synthesis of novel corrosion inhibitors and biocide metal complex nanoparticle surfactants was achieved through the reaction of sulfonamide with selenious acid to produce a quaternary ammonium salt. Platinum and cobalt surfactants were then formed by complexing the first products with platinum (II) or cobalt (II) ions. The surface properties of these surfactants were then investigated, and the free energy of form micelles (ΔG_omic) and adsorption (ΔG_oads) was determined. The obtained cationic compounds were evaluated as corrosion inhibitors for carbon steel dissolution in 1N HCl medium. The results of gravimetric and electrochemical measurements showed that the obtained inhibitors were excellent corrosion inhibitors. The anti-sulfate-reducing bacteria activity known to cause corrosion of oil pipes was obtained by the inhibition zone diameter method for the prepared compounds, which were measured against sulfate-reducing bacteria. FTIR spectra, elemental analysis, H1 NMR spectrum, and 13C labeling were performed to ensure the purity of the prepared compounds.