Radiodifluoromethylation of well-functionalized molecules.

The strategic installation of a [18F]fluorine atom at the specific position of the lead molecule is a never-ending challenge for radiochemists in their endeavour to develop novel positron emission tomography (PET) imaging applications. Although the radiosynthesis of [18F]CF2H-containing molecules has been explored in the past decade, more methods need to be explored for various well-functionalized compounds. Recently, two novel strategies of radiodifluoromethylation were reported, namely the utilization of [18F]difluorocarbene building block and frustrated Lewis pair-mediated C-18F bond formation, respectively. These methods provide an efficient radiofunctionalization of complex CF2H-containing molecules for drug discovery and PET ligand development.

Exploring opportunities to strengthen rural tuberculosis health service delivery: a qualitative study with health workers in Tibet autonomous region, China.

OBJECTIVES: This qualitative study aimed to explore opportunities to strengthen tuberculosis (TB) health service delivery from the perspectives of health workers providing TB care in Shigatse prefecture of Tibet Autonomous Region, China. DESIGN: Qualitative research, semi-structured in-depth interviews. SETTING: The TB care ecosystem in Shigatse, including primary and community care. PARTICIPANTS: Participants: 37 semi-structured interviews were conducted with village doctors (14), township doctors and nurses (14), county hospital doctors (7) and Shigatse Centre for Disease Control staff (2). RESULTS: The three main themes reported include (1) the importance of training primary and community health workers to identify people with symptoms of TB, ensure TB is diagnosed and link people with TB to further care; (2) the need to engage community health workers to ensure retention in care and adherence to TB medications; and (3) the opportunity for innovative technologies to support coordinated care, retention in care and adherence to medication in Shigatse. CONCLUSIONS: The quality of TB care could be improved across the care cascade in Tibet and other high-burden, remote settings by strengthening primary care through ongoing training, greater support and inclusion of community health workers and by leveraging technology to create a circle of care. Future formative and implementation research should include the perspectives of health workers at all levels to improve care organisation and delivery.

Asymmetric Tandem Michael Addition/Interrupted Nef Reactions of Nitromethane with Oxindole-Derived Alkenes: Enantioselective Synthesis of Spiro-polycyclic Oxindoles.

Chiral spiro-polycyclic oxindoles are valuable heterocyclic ring systems that are widely distributed in natural alkaloids and biologically active compounds. Herein, we reported an asymmetric tandem Michael addition/interrupted Nef reaction of nitromethane with oxindole-derived alkenes catalyzed by a chiral 2-aminobenzimidazole bifunctional organocatalyst. A series of novel enantiomerically enriched spiro-polycyclic oxindole derivatives bearing an oxime group were synthesized in moderate to excellent isolated yields (up to 99%) with an excellent level of enantioselectivities (up to 99% ee). Furthermore, the antiproliferation activity of the resulting oxindoles derivatives were evaluated, and compound 2d demonstrated promising anticancer properties against HCT116 (IC50 = 14.08 µM) and HT29 (IC50 = 15.46 µM) cell lines.

Effectiveness of a comprehensive package based on electronic medication monitors at improving treatment outcomes among tuberculosis patients in Tibet: a multicentre randomised controlled trial.

BACKGROUND: WHO recommends that electronic medication monitors, a form of digital adherence technology, be used as a complement to directly observed treatment (DOT) for tuberculosis, as DOT is inconvenient and costly. However, existing evidence about the effectiveness of these monitors is inconclusive. Therefore, we evaluated the effectiveness of a comprehensive package based on electronic medication monitors among patients with tuberculosis in Tibet Autonomous Region (hereafter Tibet), China. METHODS: This multicentre, randomised controlled trial recruited patients from six counties in Shigatse, Tibet. Eligible participants had drug-susceptible tuberculosis and were aged 15 years or older when starting standard tuberculosis treatment. Tuberculosis doctors recruited patients from the public tuberculosis dispensary in each county and the study statistician randomly assigned them to the intervention or control group based on the predetermined randomised allocation sequence. Intervention patients received an electronic medication monitor box. The box included audio medication-adherence reminders and recorded box-opening data, which were transmitted to a cloud-based server and were accessible to health-care providers to allow remote adherence monitoring. A linked smartphone app enabled text, audio, and video communication between patients and health-care providers. Patients were also provided with a free data plan. Patients selected a treatment supporter (often a family member) who was trained to support patients with using the electronic medication monitor and app. Patients in the control group received usual care plus a deactivated electronic medication monitor, which only recorded and transmitted box-opening data that was not made available to health-care providers. The control group also had no access to the app or trained treatment supporters. The primary outcome was a binary indicator of poor monthly adherence, defined as missing 20% or more of planned doses in the treatment month, measured using electronic medication monitor opening data, and verified by counting used medication blister packages during consultations. We recorded other secondary treatment outcomes based on national tuberculosis reporting data. We analysed the primary outcome based on the intention-to-treat population. This trial is registered at ISRCTN, 52132803. FINDINGS: Between Nov 17, 2018, and April 5, 2021, 278 patients were enrolled into the study. 143 patients were randomly assigned to the intervention group and 135 patients to the control group. Follow-up ended when the final patient completed treatment on Oct 4, 2021. In the intervention group, 87 (10%) of the 854 treatment months showed poor adherence compared with 290 (37%) of the 795 months in the control group. The corresponding adjusted risk difference for the intervention versus control was -29·2 percentage points (95% CI -35·3 to -22·2; p<0·0001). Five of the six secondary treatment outcomes also showed clear improvements, including treatment success, which was found for 133 (94%) of the 142 individuals in the intervention arm and 98 (73%) of the 134 individuals in the control arm, with an adjusted risk difference of 21 percentage points (95% CI 12·4-29·4); p<0·0001. INTERPRETATION: The interventions were effective at improving tuberculosis treatment adherence and outcomes, and the trial suggests that a comprehensive package involving electronic medication monitors might positively affect tuberculosis programmes in high-burden and low-resource settings. FUNDING: TB REACH.

Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2).

Parkinson's disease (PD) is one of the most highly debilitating neurodegenerative disorders, which affects millions of people worldwide, and leucine-rich repeat kinase 2 (LRRK2) mutations have been involved in the pathogenesis of PD. Developing a potent LRRK2 positron emission tomography (PET) tracer would allow for in vivo visualization of LRRK2 distribution and expression in PD patients. In this work, we present the facile synthesis of two potent and selective LRRK2 radioligands [11C]3 ([11C]PF-06447475) and [18F]4 ([18F]PF-06455943). Both radioligands exhibited favorable brain uptake and specific bindings in rodent autoradiography and PET imaging studies. More importantly, [18F]4 demonstrated significantly higher brain uptake in the transgenic LRRK2-G2019S mutant and lipopolysaccharide (LPS)-injected mouse models. This work may serve as a roadmap for the future design of potent LRRK2 PET tracers.

Construction of rBCG carrying the IL-2-BZLF1 fusion gene and its immunological function.

In this research, a recombinant Bacillus Calmette Guerin (rBCG) vector vaccine carrying a human IL-2 and EBV BZLF1 fusion gene (IL-2-BZLF1-rBCG) was constructed. The IL-2-BZLF1-rBCG construct was successfully generated and stably expressed the IL-2 and BZLF1 proteins. IL-2-BZLF1-rBCG activated the immune system and promoted the secretion of IFN-γ and TNF-α by CD4+ and CD8+ T cells. IL-2-BZLF1-rBCG activated lymphocytes to effectively kill EBV-positive NPC cells in vitro. Additionally, IL-2-BZLF1-rBCG stimulated the proliferation of NK cells and lymphocytes in vivo, activated related immune responses, and effectively treated EBV-positive NPC. The immune response to and pharmacological effect of IL-2-BZLF1-rBCG were explored in vitro and in vivo to provide a theoretical and experimental basis for the prevention and treatment of EBV-positive tumors with an rBCG vector vaccine. KEY POINTS: • rBCG with human IL-2 and BZLF1 of EB virus was constructed • The IL-2-BZLF1 fusion gene was stably expressed with rBCG • rBCG with IL-2-BZLF1 has an obvious immune response in vitro and in vivo.

Preclinical Evaluation of Azabenzimidazole-Based PET Radioligands for γ-8 Dependent Transmembrane AMPA Receptor Regulatory Protein Imaging.

AMPA glutamate receptors (AMPARs) play a pivotal role in excitatory neurotransmission, particularly in the hippocampus where the TARP γ-8 subunit is enriched and serves as a target for emerging anti-epileptic drugs. To enable in vivo visualization of TARP γ-8 distribution and expression by positron emission tomography (PET), this study focuses on the development of novel 18 F-labeled TARP γ-8 inhibitors and their corresponding precursors, stemming from the azabenzimidazole scaffold. The resulting radioligands [18 F]TARP-2204 and [18 F]TARP-2205 were successfully synthesized with acceptable radiochemical yield, high molar activity, and excellent radiochemical purity. In vitro autoradiography demonstrates high level of specific binding of [18 F]TARP-2205 to TARP γ-8 in both rat and nonhuman primate brain tissues. However, unexpected radiodefluorination in PET imaging studies of rodents emphasizes the need for further structural refinement. This work serves as an excellent starting point for the development of future 18 F-labeled TARP γ-8 PET tracers, offering valuable insights into medicinal chemistry design, radiosynthesis and subsequent PET evaluation.

Synthesis and Biological Evaluation of Enantiomerically Pure (R)- and (S)-[18F]OF-NB1 for Imaging the GluN2B Subunit-Containing NMDA Receptors.

GluN2B subunit-containing N-methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. The aim of this study was to develop a novel synthetic approach that allows an enantiomerically pure radiosynthesis of the previously reported PET radioligands (R)-[18F]OF-NB1 and (S)-[18F]OF-NB1 as well as to assess their in vitro and in vivo performance characteristics for imaging the GluN2B subunit-containing NMDA receptor in rodents. A novel synthetic approach was successfully developed, which allows for the enantiomerically pure radiosynthesis of (R)-[18F]OF-NB1 and (S)-[18F]OF-NB1 and the translation of the probe to the clinic. While both enantiomers were selective over sigma2 receptors in vitro and in vivo, (R)-[18F]OF-NB1 showed superior GluN2B subunit specificity by in vitro autoradiography and higher volumes of distribution in the rodent brain by small animal PET studies.

Field validation of different intervention modes for the potential transmission risk of schistosomiasis during post-transmission interruption phase.

OBJECTIVE: Precision interventions have been proposed in transmission-interrupted areas to further reduce the potential transmission risk of schistosomiasis. This study aimed to evaluate the effects of different interventions modes for potential transmission risk control. METHODS: Three groups of schistosomiasis-endemic villages were selected in Jiangling county, Hubei province. After baseline surveys in 2020, three intervention models were employed in 2021 and 2022. In Model 1, Oncomelania hupensis snail control in key settings and an integrated strategy with an emphasis on the infectious sources managing was employed. In Model 2, an integrated health education-led strategy with an emphasis on infectious source management was employed. In Model 3, only the integrated strategy with an emphasis on infectious source management was employed. The effects of the different intervention models were examined with multiple indicators after 2 years of intervention using the entropy-weighted technique for order of preference by similarity to ideal solution (TOPSIS), rank-sum ratio (RSR) and fuzzy combination model of entropy-weighted TOPSIS and RSR. RESULTS: Entropy-weighted TOPSIS modeling showed that the Ci values of Model 2 were 0.4434, 0.2759, and 0.3069 in the three pilot villages, Ci values were larger, with top comprehensive ranking. The results of the RSR method showed that the RSR values of Model 2 were 0.75, 0.708, and 0.736 in the three pilot villages, with top comprehensive ranking. The results from the fuzzy combination model of entropy-weighted TOPSIS and RSR showed that implementation of Model 2 resulted in the highest comprehensive ranking among the three models in the three pilot villages under Ci: RSR = 0.1: 0.9, Ci: RSR = 0.5: 0.5 and Ci: RSR = 0.9: 0.1. CONCLUSION: The integrated health education-led strategy with an emphasis on infectious source management was the optimal model to manage the risk of transmission of schistosomiasis during the post-transmission interruption phase.

Evaluation of thiadiazine-based PET radioligands for imaging the AMPA receptor.

As a subclass of ionotropic glutamate receptors (iGluRs), α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been implicated in various neurological disorders and neurodegenerative diseases. To further our understanding of AMPA receptor-related disorders in the central nervous system (CNS), it is important to be able to image and quantify AMPA receptors in vivo. In this study, we identified a novel F-containing AMPA positive allosteric modulator (PAM) 6 as a potential lead compound. Molecular docking studies and CNS PET multi-parameter optimization (MPO) analysis were used to predict the absorption, distribution, metabolism, and excretion (ADME) characteristics of 6 as a PET probe. The resulting PET probe, [18F]6 (codename [18F]AMPA-2109), was successfully radiolabeled and demonstrated excellent blood-brain barrier (BBB) permeability and high brain uptake in rodents and non-human primates. However, [18F]6 did not show substantial specific binding in the rodent or non-human primate brain. Further medicinal chemistry efforts are necessary to improve specific binding, and our work may serve as a starting point for the design of novel 18F-labeled AMPA receptor-targeted PET radioligands aimed for clinical translation.

Evaluation of [18F]RoSMA-18-d6 as a CB2 PET Radioligand in Nonhuman Primates.

The cannabinoid type 2 receptor (CB2) has been implicated in a variety of central and peripheral inflammatory diseases, prompting significant interest in the development of CB2-targeted diagnostic and therapeutic agents. A validated positron emission tomography (PET) radioligand for imaging CB2 in the living human brain as well as in peripheral tissues is currently lacking. As part of our research program, we have recently identified the trisubstituted pyridine, [18F]RoSMA-18-d6, which proved to be highly suitable for in vitro and in vivo mapping of CB2 in rodents. The aim of this study was to assess the performance characteristics of [18F]RoSMA-18-d6 in nonhuman primates (NHPs) to pave the way for clinical translation. [18F]RoSMA-18-d6 was synthesized from the respective tosylate precursor according to previously reported procedures. In vitro autoradiograms with NHP spleen tissue sections revealed a high binding of [18F]RoSMA-18-d6 to the CB2-rich NHP spleen, which was significantly blocked by coincubation with the commercially available CB2 ligand, GW405833 (10 µM). In contrast, no specific binding was observed by in vitro autoradiography with NHP brain sections, which was in agreement with the notion of a CB2-deficient healthy mammalian brain. In vitro findings were corroborated by PET imaging experiments in NHPs, where [18F]RoSMA-18-d6 uptake in the spleen was dose-dependently attenuated with 1 and 5 mg/kg GW405833, while no specific brain signal was observed. Remarkably, we observed tracer uptake and retention in the NHP spinal cord, which was reduced by GW405833 blockade, pointing toward a potential utility of [18F]RoSMA-18-d6 in probing CB2-expressing cells in the bone marrow. If these observations are substantiated in NHP models of enhanced leukocyte proliferation in the bone marrow, [18F]RoSMA-18-d6 may serve as a valuable marker for hematopoietic activity in various pathologies. In conclusion, [18F]RoSMA-18-d6 proved to be a suitable PET radioligand for imaging CB2 in NHPs, supporting its translation to humans.

Development of Novel 11C-Labeled Selective Orexin-2 Receptor Radioligands for Positron Emission Tomography Imaging.

Orexin 2 receptors (OX2R) represent a vital subtype of orexin receptors intricately involved in the regulation of wakefulness, arousal, and sleep-wake cycles. Despite their importance, there are currently no positron emission tomography (PET) tracers available for imaging the OX2R in vivo. Herein, we report [11C]1 ([11C]OX2-2201) and [11C]2 ([11C]OX2-2202) as novel PET ligands. Both compounds 1 (Ki = 3.6 nM) and 2 (Ki = 2.2 nM) have excellent binding affinity activities toward OX2R and target selectivity (OX2/OX1 > 600 folds). In vitro autoradiography in the rat brain suggested good to excellent in vitro binding specificity for [11C]1 and [11C]2. PET imaging in rat brains indicated that the low brain uptake of [11C]2 may be due to P-glycoprotein and/or breast cancer resistance protein efflux interaction and/or low passive permeability. Continuous effort in medicinal chemistry optimization is necessary to improve the brain permeability of this scaffold.

The mechanisms underlying the negative effect of socioeconomic status on depressive symptoms among older adults: The roles of social support and living arrangement.

OBJECTIVES: Previous studies have found an association between socioeconomic status (SES) and depressive symptoms among older adults, however the mechanisms underlying this association remained unclear. This study aimed to examine the mediating role of social support and the moderating role of living arrangement in the association between SES and depressive symptoms. METHODS: Data was collected from the 2020 Household Health Interview Survey in Taian city, Shandong Province, China. A total of 3896 older adults aged 60 and above were included in this study. Depressive symptoms was measured by the Patient health Questionnaire-9 (PHQ-9), Social support by the Multidimensional Scale of Perceived Social Support (MSPSS), and other variables by related demographic scales. The moderated mediation model was examined using HAYES PROCESS 3.5. RESULTS: SES negatively predicted depressive symptoms among older adults, and social support could mediate this association. Living arrangement played a moderating role in the relationship between social support and depressive symptoms (the second half of the mediating effect), and the effect was stronger among older adults who lived alone. CONCLUSIONS: Social support partially mediated the relationship between SES and depressive symptoms among older adults, and living alone strengthened the effect of social support on depressive symptoms. Interventions that address older adults' social support and living arrangement may ameliorate depressive symptoms among older adults.

Imaging Cholinergic Receptors in the Brain by Positron Emission Tomography.

Cholinergic receptors represent a promising class of diagnostic and therapeutic targets due to their significant involvement in cognitive decline associated with neurological disorders and neurodegenerative diseases as well as cardiovascular impairment. Positron emission tomography (PET) is a noninvasive molecular imaging tool that has helped to shed light on the roles these receptors play in disease development and their diverse functions throughout the central nervous system (CNS). In recent years, there has been a notable advancement in the development of PET probes targeting cholinergic receptors. The purpose of this review is to provide a comprehensive overview of the recent progress in the development of these PET probes for cholinergic receptors with a specific focus on ligand structure, radiochemistry, and pharmacology as well as in vivo performance and applications in neuroimaging. The review covers the structural design, pharmacological properties, radiosynthesis approaches, and preclinical and clinical evaluations of current state-of-the-art PET probes for cholinergic receptors.

Differential responses of disease-related GRIN variants located in pore-forming M2 domain of N-methyl-D-aspartate receptor to FDA-approved inhibitors.

N-methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptors, mediate a slow component of excitatory synaptic transmission in the central nervous system and play a key role in normal brain function and development. Genetic variations in GRIN genes encoding NMDAR subunits that alter the receptor's functional characteristics are associated with a wide range of neurological and neuropsychiatric conditions. Pathological GRIN variants located in the M2 re-entrant loop lining the channel pore cause significant functional changes, the most consequential alteration being a reduction in voltage-dependent Mg2+ inhibition. Voltage-dependent Mg2+ block is a unique feature of NMDAR biology whereby channel activation requires both ligand binding and postsynaptic membrane depolarization. Thus, loss of NMDAR Mg2+ block will have a profound impact on synaptic function and plasticity. Here, we choose 11 missense variants within the GRIN1, GRIN2A, and GRIN2B genes that alter residues located in the M2 loop and significantly reduce Mg2+ inhibition. Each variant was evaluated for tolerance to genetic variation using the 3-dimensional structure and assessed for functional rescue pharmacology via electrophysiological recordings. Three FDA-approved NMDAR drugs-memantine, dextromethorphan, and ketamine-were chosen based on their ability to bind near the M2 re-entrant loop, potentially rectifying dysregulated NMDAR function by supplementing the reduced voltage-dependent Mg2+ block. These results provide insight of structural determinants of FDA-approved NMDAR drugs at their binding sites in the channel pore and may further define conditions necessary for the use of such agents as potential rescue pharmacology.

Sentinel Surveillance of Schistosomiasis - China, 2021.

Introduction: This report analyzes the national surveillance data for schistosomiasis in 2021 to understand the current status and provide evidence for further policy actions to promote elimination. This analysis is in line with the National Surveillance Plan of Schistosomiasis, which was revised in 2020 to adapt to the new stage of moving towards elimination. Methods: Data from the 2021 national surveillance of schistosomiasis in humans, livestock, and snails were collected from 13 provincial-level administrative divisions (PLADs) and analyzed using descriptive epidemiological methodology. The antibody-positive rate and area of newly discovered and re-emergent snail habitats were calculated. Results: In 2021, a total of 31,661 local residents and 101,558 transient population were screened for antibodies using indirect hemagglutination assay (IHA). Of those who tested positive, 745 local residents and 438 transient population underwent further parasitological examination, with only one stool-positive result in the transient population. Additionally, 12,966 livestock were examined using the miracidia hatching test, with no positives detected. The total area of newly discovered and re-emergent snail habitats was 957,702 m2 and 4,381,617 m2, respectively. No infected snails were found using the microscopic dissection method, but six pooled snail samples were reported as positive using the loop-mediated isothermal amplification method for detecting specific sequences of Schistosoma. japonicum, in Anhui and Jiangxi Provinces. Conclusions: The prevalence of schistosomiasis among humans and livestock was found to be low, however, a potential transmission risk was identified in certain areas. To reduce the risk of transmission, a comprehensive control strategy should be continued and new techniques should be implemented in the surveillance and early warning system.

Oncomelania hupensis Distribution and Schistosomiasis Transmission Risk in Different Environments under Field Conditions.

The goal of schistosomiasis prevention and control in China is shifting from transmission interruption to elimination. However, the area inhabited by the intermediate host, the snail Oncomelania hupensis, has not changed much in recent years. Different environmental types have different impacts on snail breeding, and understanding these differences is conducive to improving the efficiency of snail monitoring and control and to saving resources. Based on previous epidemiological data, we selected 199 villages in 2020 and 269 villages in 2021 from transmission control, transmission interruption, and elimination areas of snail breeding. Snail surveys were conducted in selected villages using systematic sampling and/or environmental sampling methods in six types of snail-breeding environments (canals, ponds, paddy fields, dry lands, bottomlands, and undefined environments). All live snails collected from the field were evaluated for Schistosoma japonicum infection using the microscopic dissection method, and a subsample of snails was subjected to loop-mediated isothermal amplification (LAMP) to assess the presence of S. japonicum infection. Snail distribution data and infection rate and nucleic acid positive rate of schistosomes in snails were calculated and analyzed. The 2-year survey covered 29,493 ha of the environment, in which 12,313 ha of snail habitats were detected. In total, 51.16 ha of new snail habitats and 107.76 ha of re-emergent snail habitats were identified during the survey. The occurrence rate of snails in canals (10.04%, 95% CI: 9.88-10.20%) and undefined environments (20.66%, 95% CI: 19.64-21.67%) was relatively high in 2020, and the density of snails in bottomlands (0.39, 95% CI: 0.28-0.50) and undefined environments (0.43, 95% CI: 0.14-1.60) was relatively high in 2021. Of the 227,355 live snails collected in this study, none were S. japonicum-positive as determined by microscopy. Of the 20,131 pooled samples, however, 5 were S. japonicum-positive based on LAMP analysis, and they were distributed in three environmental types: 3 in bottomland, 1 in dry land, and 1 in a canal. The bottomland environment has a high risk of schistosomiasis transmission because it contains a large area of newly emerging and re-emerging snail habitats, and it also had the most breeding snails infected with S. japonicum. Thus, this habitat type should be the key target for snail monitoring and early warning and for the prevention and control of schistosomiasis.

Impact of the National Wetland Park in the Poyang Lake Area on Oncomelania hupensis, the Intermediate Host of Schistoma japonicum.

In this study, we aimed to understand the influence of ecotourism on the distribution of Oncomelania hupensis and to provide a scientific basis for formulating effective snail control methods in tourism development areas. Poyang Lake National Wetland Park was selected as the pilot area, and sampling surveys were conducted based on comprehensive and detailed investigations of all historical and suspected snail environments according to map data to determine the snail distribution and analyze the impact of tourism development. The results showed that from 2011 to 2021, the positive rates of blood tests and fecal tests tended to decrease among residents of the Poyang Lake area. The positive rates of blood tests and fecal tests in livestock also tended to decrease. The average density of O. hupensis snails decreased, and no schistosomes were detected during infection monitoring in Poyang Lake. The local economy rapidly grew after the development of tourism. The development of ecotourism projects in Poyang Lake National Wetland Park increased the transfer frequency of boats, recreational equipment, and people, but it did not increase the risk of schistosomiasis transmission or the spread of O. hupensis snails. Prevention and monitoring only need to be strengthened in low-endemic schistosomiasis areas to effectively promote economic development due to tourism activities without affecting the health of residents.

Evaluation of [18F]Favipiravir in Rodents and Nonhuman Primates (NHP) with Positron Emission Tomography.

The COVID-19 pandemic has posed a significant challenge to global public health. In response, the search for specific antiviral drugs that can effectively treat the disease caused by the SARS-CoV-2 virus has become a priority. While significant progress has been made in this regard, much work remains to address this ongoing crisis effectively. Favipiravir is an antiviral drug initially developed for the treatment of influenza and has received approval for emergency use for COVID-19 in many countries. A better understanding of the biodistribution and pharmacokinetics of Favipiravir in vivo would facilitate the development and translation of clinical antiviral drugs for COVID-19. Herein, we report the evaluation of [18F]Favipiravir in naive mice, transgenic mice models of Alzheimer's disease, and nonhuman primates (NHP) with positron emission tomography (PET). The [18F]Favipiravir was obtained in an overall decay-corrected radiochemical yield of 29% with a molar activity of 25 GBq/µmol at the end of synthesis (EOS). PET imaging in naive mice, transgenic mice models of Alzheimer's disease, and nonhuman primates revealed a low initial brain uptake, followed by a slow washout of [18F]Favipiravir in vivo. The [18F]Favipiravir was eliminated by a combination of hepatobiliary and urinary excretion. The low brain uptake was probably attributed to the low lipophilicity and low passive permeability of the drug. We hope this proof-of-concept study will provide a unique feature to study antiviral drugs using their corresponding isotopologues by PET.

Quantitative assessment of translocator protein (TSPO) in the non-human primate brain and clinical translation of [18F]LW223 as a TSPO-targeted PET radioligand.

OBJECTIVES: Translocator protein 18 kDa (TSPO) positron emission tomography (PET) can be harnessed for the non-invasive detection of macrophage-driven inflammation. [18F]LW223, a newly reported TSPO PET tracer which was insensitive to rs6971 polymorphism, showed favorable performance characteristics in a recent imaging study involving a rat myocardial infarction model. To enable quantitative neuroimaging with [18F]LW223, we conducted kinetic analysis in the non-human primate (NHP) brain. Further, we sought to assess the utility of [18F]LW223-based TSPO imaging in a first-in-human study. METHODS: Radiosynthesis of [18F]LW223 was accomplished on an automated module, whereas molar activities, stability in formulation, lipophilicity and unbound free fraction (fu) of the probe were measured. Brain penetration and target specificity of [18F]LW223 in NHPs were corroborated by PET-MR imaging under baseline and pre-blocking conditions using the validated TSPO inhibitor, (R)-PK11195, at doses ranging from 5 to 10 mg/kg. Kinetic modeling was performed using one-tissue compartment model (1TCM), two-tissue compartment model (2TCM) and Logan graphical analyses, using dynamic PET data acquisition, arterial blood collection and metabolic stability testing. Clinical PET scans were performed in two healthy volunteers (HVs). Regional brain standard uptake value ratio (SUVr) was assessed for different time intervals. RESULTS: [18F]LW223 was synthesized in non-decay corrected radiochemical yields (n.d.c. RCYs) of 33.3 ± 6.5% with molar activities ranging from 1.8 ± 0.7 Ci/µmol (n = 11). [18F]LW223 was stable in formulation for up to 4 h and LogD7.4 of 2.31 ± 0.13 (n = 6) and fu of 5.80 ± 1.42% (n = 6) were determined. [18F]LW223 exhibited good brain penetration in NHPs, with a peak SUV value of ca. 1.79 in the whole brain. Pre-treatment with (R)-PK11195 substantially accelerated the washout and attenuated the area under the time-activity curve, indicating in vivo specificity of [18F]LW223 towards TSPO. Kinetic modeling demonstrated that 2TCM was the most suitable model for [18F]LW223-based neuroimaging. Global transfer rate constants (K1) and total volumes of distribution (VT) were found to be 0.10 ± 0.01 mL/cm3/min and 2.30 ± 0.17 mL/cm3, respectively. Dynamic PET data analyses across distinct time windows revealed that the VT values were relatively stable after 60 min post-injection. In a preliminary clinical study with two healthy volunteers, [18F]LW223 exhibited good brain uptake and considerable tracer retention across all analyzed brain regions. Of note, an excellent correlation between SUVr with VT was obtained when assessing the time interval from 20 to 40 min post tracer injection (SUVr(20-40 min), R2 = 0.94, p < 0.0001), suggesting this time window may be suitable to estimate specific binding to TSPO in human brain. CONCLUSION: Our findings indicate that [18F]LW223 is suitable for quantitative TSPO-targeted PET imaging in higher species. Employing state-of-the-art kinetic modeling, we found that [18F]LW223 was effective in mapping TSPO throughout the NHP brain, with best model fits obtained from 2TCM and Logan graphical analyses. Overall, our results indicate that [18F]LW223 exhibits favorable tracer performance characteristics in higher species, and this novel imaging tool may hold promise to provide effective neuroinflammation imaging in patients with neurological disease.