Biological Evaluation and Binding Mechanism of 5-HT7 Specific Arylpiperazinyl-Alkyl Benzothiazolone: Radiobiology and Photo-physical Studies.

Diversely substituted methoxy derivatives of arylpiperazinyl-alkyl benzothiazolone has been evaluated as specific probe for 5HT7. To determine the best methoxy derivative for 5HT7 receptor affinity, we synthesised a number of 2-benzothiazolone arylalkyl piperazine derivatives. In-vitro/vivo studies with C-2 substituted [11C]ABT showed 5HT7 specific binding. The radiochemical purity of [11C]ABT was found to be more than 99% with radiochemical stability persistence for more than 1.5 hr at 25 °C. The interaction of BSA and ABT has been analysed by photophysical studies for better understanding of properties such as adsortion, distribution, metabolism and elemination (ADME). The interaction between ABT and BSA was analyzed by using the UV-vis and fluorescence spectra. UV-vis spectra analyzed the changes in primary structure of BSA on its interaction with ABT. ABT showed quenched fluorescence emission intensity of tryptophan residues in BSA via static quenching mechanism. This study might help to understand how ABT binds to serum protein or subsequently to know the ADME of this drug candidate.

Adsorption characteristics of magnetized biochar derived from Citrus limetta peels.

Agro-industrial waste is an alarming issue that needs to be addressed. Waste valorization is an effective technique to deal with such effectively. Synthesis of biochar from fruit waste is one of the emerging approaches for adsorption, energy storage, air purification, catalysis, and biogas production trending these days. Magnetized Citrus limetta biochar (MCLB) was synthesized from Citrus limetta peels and was magnetized using iron oxide. Magnetization of biochar increases its functionalities as well as makes its separation easy. The removal of Methylene Blue (MB) dye from an aqueous solution is achieved through the use of MCLB. Methylene Blue is a prominent and widely used cationic-azo dye in the textile and printing industries. The accumulation of MB in wastewater is the major problem as MB is reported as a carcinogenic agent. The removal of MB dye with MCLB was analyzed by adsorption studies, wherein the effect of factors influencing adsorption such as initial concentration of MB dye, MCLB dosage, the effect of pH, contact time, and adsorption isotherms were studied. Characterization of MCLB was carried out using various techniques, such as FTIR, VSM, XRD, SEM, RAMAN, and Zeta potential. The adsorption isotherm mechanism was well explained with the non-linear Langmuir isotherm model resulting in a good adsorption capacity (qe = 41.57 mg/g) of MCLB when MB (co = 60 mg/L, pH ~ 6.8, T = 273K). The thermodynamics analysis revealed that MB's spontaneous and endothermic adsorption onto the MCLB surface followed pseudo-second-order kinetics. The results obtained from this study suggest that the magnetized biochar derived from Citrus limetta peels has a wide range of potential applications in the treatment of dyeing wastewater.

Recent advances in conducting polymer-based magnetic nanosorbents for dyes and heavy metal removal: fabrication, applications, and perspective.

Globally, treating and disposing of industrial pollutants is a techno-economic challenge. Industries' large production of harmful heavy metal ions (HMIs) and dyes and inappropriate disposal worsen water contamination. Much attention is required on the development of efficient and cost-effective technologies and approaches for removing toxic HMIs and dyes from wastewater as they pose a severe threat to public health and aquatic ecosystems. Due to the proven superiority of adsorption over other alternative methods, various nanosorbents have been developed for the efficient removal of HMIs and dyes from wastewater and aqueous solutions. Being a good adsorbent, conducting polymer-based magnetic nanocomposites (CP-MNCPs) has drawn more attention for HMIs and dye removal. Conductive polymers' pH-responsiveness makes CP-MNCP ideal for wastewater treatment. The composite material absorbed dyes and/or HMIs from contaminated water could be removed by changing the pH. Here, we review the production strategies and applications of CP-MNCPs for HMIs and dye removal. The review also sheds light on the adsorption mechanism, adsorption efficiency, kinetic and adsorption models, and regeneration capacity of the various CP-MNCPs. To date, various modifications to conducting polymers (CPs) have been explored to improve the adsorption properties. It is evident from the literature survey that the combination of SiO2, graphene oxide (GO), and multi-walled carbon nanotubes (MWCNTs) with CPs-MNCPs enhances the adsorption capacity of nanocomposites to a large extent, so future research should lean toward the development of cost-effective hybrid CPs-nanocomposites.

Development and challenges in the discovery of 5-HT1A and 5-HT7 receptor ligands.

Serotonin (5-hydroxytryptamine) is a small molecule that acts both in the central and peripheral nervous system as a neurotransmitter and a hormone, respectively. Serotonin is synthesized via a multi-stage pathway beginning with l-tryptophan, which is converted by an enzyme called tryptophan hydroxylase into L-5-Hydroxytryptophan. It is well-known for its significance in the control of mood, anxiety, depression, and insomnia as well as in normal human functions such as sleep, sexual activity, and appetite. Thus, for medical chemists and pharmaceutical firms, serotonin is one of the most desirable targets. Among the seven different classes of serotonin receptors, the 5-HT1A was one of the first discovered serotonin receptors, and the 5-HT7 was the last addition to the serotonin receptor family. Both the classes were thoroughly examined. 5-HT1A neurotransmission-related dysfunctions are linked to many psychological conditions such as anxiety, depression, and movement disorders. 5-HT7 is a member of the cell surface receptor GPCR superfamily and is regulated by the serotonin neurotransmitter. It has been the focus of intensive research efforts since its discovery, which was prompted by its presence in functionally important regions of the brain. The thalamus and hypothalamus have the highest 5-HT7 receptor densities. They are also found in the hippocampus and cortex at higher densities. Thermoregulation, circadian rhythm, learning and memory, and sleep are all associated with the 5-HT7 receptor. It is also suspected that this receptor may be involved in the control of mood, indicating that it may be a beneficial target for depression treatment. Several differently structured molecules such as aminotetralins, ergolines, arylpiperazines, indolylalkylamines, aporphines, and aryloxyalkyl-amines are known to bind to 5-HT1A and 5-HT7 receptor sites. In brain serotonin receptors 5-HT1A and 5-HT7 are strongly co-expressed in regions involved in depression. However, their functional interaction has not been identified. An overview of the 5-HT1A and 5-HT7 receptor ligands belonging to different chemical groups is mentioned in this review.

Acetamidobenzoxazolone scaffold as a promising translocator protein (18 kDa, TSPO) marker for neuroinflammation imaging: Advancement in last decennial period.

Inflammation has been linked to the onset and progression of a wide range of neuropathological disorders. The well-conserved outer mitochondrial membrane 18 kDa translocator protein (TSPO) is perceived as an in vivo neuroinflammation marker. A dearth of a reference region, genetic disparity influencing the ligand's affinity for TSPO, and a substantial signal in the endothelium of the brain veins contributes toward complications in quantifying TSPO positron emission tomography (PET) image. Up to the present time several radiotracers based on different pharmacophore such as (R)[11 C]PK11195, [18 F]DPA714, [11 C]PBR28, [11 C]ER176, and many more have been recognized for envisaging the prominent TSPO level observed in neurological conditions. Recently acetamidobenzoxazolone (ABO) scaffold, a bicyclic ring system composed of a phenyl ring fused to a carbamate and its substituted radiolabelled analogues especially at C-5 position has evidenced encouraging outcomes as next generation of TSPO PET ligands. Diverse ABO framework-based TSPO ligands have been designed embracing imperative aspects such as lipophilicity, metabolic profile, and capability to penetrate the blood-brain barrier apart from least effect of polymorphism (rs6971). Over the years numerous systematic literature reviews compiling different structural class of TSPO ligands characterized on the grounds of their binding affinity and metabolite profile have been reported but none is especially focused toward a fascinating benzoxazolone scaffold. This review exclusively bestows an overview of the recent advancements on ABO derivatives with neuroinflammation imaging potential and emphases on the structural features accountable for visualizing TSPO in-vivo with collation of published reports during last 10 years.

Current Status of Our Understanding for Brain Integrated Functions and its Energetics.

Human/animal brain is a unique organ with substantially high metabolism but it contains no energy reserve that is the reason it requires continuous supply of O2 and energy fluxes through CBF. The main source of energy remains glucose as the other biomolecules do not able to cross the blood-brain barrier. The speed of glucose metabolism is heterogeneous throughout the brain. One of the major flux consumption is Neuron-astrocyte cycling of glutamate and glutamine in glutamatergic neurons (approximately 80% of glucose metabolism in brain). The quantification of cellular glucose and other related substrate in resting, activated state can be analyzed through [18 F]FDG -positron-emission tomography (studying CMRglc) and [13 C/31P -MRS: for neuroenergetics & neurotransmitter cycling &31P-MRS: for energy induction & redox state). Merging basic in vitro studies with these techniques will help to develop new treatment paradigms for human brain diseased conditions.

The 18-kDa Translocator Protein PET Tracers as a Diagnostic Marker for Neuroinflammation: Development and Current Standing.

Translocator protein (TSPO, 18 kDa) is an evolutionary, well-preserved, and tryptophan-rich 169-amino-acid protein which localizes on the contact sites between the outer and inner mitochondrial membranes of steroid-synthesizing cells. This mitochondrial protein is implicated in an extensive range of cellular activities, including steroid synthesis, cholesterol transport, apoptosis, mitochondrial respiration, and cell proliferation. The upregulation of TSPO is well documented in diverse disease conditions including neuroinflammation, cancer, brain injury, and inflammation in peripheral organs. On the basis of these outcomes, TSPO has been assumed to be a fascinating subcellular target for early stage imaging of the diseased state and for therapeutic purposes. The main outline of this Review is to give an update on dealing with the advances made in TSPO PET tracers for neuroinflammation, synchronously emphasizing the approaches applied for the design and advancement of new tracers with reference to their structure-activity relationship (SAR).

Realizing quasi-monochromatic switchable thermal emission from electro-optically induced topological phase transitions.

Explorations into the photonic analogs of topological materials have garnered significant research interest due to their application potential. Particularly in planar systems, the prospects of engendering extinguishable topological states can have wide-ranging implications. With an objective of employing these concepts for thermal emission engineering, here, we design and numerically investigate a quasi-monochromatic highly directional mid-infrared source elicited from inversion symmetry-protected topological interface states. Notably, by relying on the architecture of electro-optic effect-induced topological phase transitions, we introduce the possibility of ultrafast switching of thermal radiation. These reversible phase transitions, being free from carrier transport are inherently fast and evoke thermal emission modulation with a modulation depth upto 0.99. Specifically, our platform exhibits a near-perfect extinguishable spectral emission peak at [Formula: see text]m with a quality factor of over 18500, displaying negligible parasitic emissions. Furthermore, the optimized interface state manifests itself for only one of the polarization modes, resulting in polarized emission under resonance conditions. To establish a methodical approach to parameter optimization, we also model our platform as a leaky mode resonator using the framework of temporal coupled-mode theory. We believe, our findings can provide a way forward in establishing complete control over the optical characteristics of the infrared thermal emitters.

Receptor mapping using methoxy phenyl piperazine derivative: Preclinical PET imaging.

This study aimed at assessing 2-methoxyphenyl piperazine derivative for its binding specificity and suitability in mapping metabotropic glutamate receptor subtype 1, which is implicated in several neuropsychiatric disorders. N-(2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl)-N-methylpyridin-2-amine was synthesised and evaluated for brain imaging subsequent to radiolabelling with [11C] radioisotope via methylation process in 98.9% purity and 52 ± 6% yield (decay corrected). The specific activity was in the range of 72-93 GBq/µmol. The haemolysis of blood was 2-5% for initial 4 hr and remained < 10% after 24 h of incubation indicating low toxicity. In vitro autoradiograms after coincubation with unlabelled ligand confirmed the high uptake of the PET radioligand in the mGluR1 receptor rich regions. The PET as well as biodistribution studies also showed high activity in the brain with a direct correlation between receptor abundance distribution pattern and tracer activity. The biodistribution analyses revealed initial high brain uptake (4.18 ± 0.48). The highest uptake was found in cerebellum (SUV 4.7 ± 0.2), followed by thalamus (SUV 3.5 ± 0.1), and striatum (SUV 3 ± 0.1). In contrast, pons had negligible tracer activity. The high uptake observed in all the regions with known mGluR1 activity indicates suitability of the ligand for mGluR1 imaging.

Synthesis and evaluation of technetium-99m labelled 1-(2-methoxyphenyl)piperazine derivative for single photon emission computed tomography imaging for targeting 5-HT1A.

Quantitative changes in expression level of 5HT1A are somewhere related to common neurological disorders such as anxiety, major depression and schizophrenia. We have designed EDTA conjugated SPECT imaging probe for localization of 5HT1A receptor in brain. For designing SPECT probe we have employed the concept of bivalent approach and a homodimeric system with desirable pharmacokinetics of 5HT1A imaging. 99mTc-EDHT was also evaluated for its stability through serum stability assay and glutathione challenge experiment. Biodistribution study showed the highest accumulation of radioactivity in kidney which depicted the renal mode of excretion from the body. However in brain the uptake of 1.21% ID per gram was observed in initial 5 min of drug administration. On blocking the receptor this percent get decreased to 0.97% ID per gram. The regional distribution in brain was also performed which showed the accumulation of drug in cerebellum, cortex and hippocampus part, which are already known for 5HT1A expression. Dynamic study in rabbit is also in support of results derived from biodistribution and blood kinetics experiment. These finding suggest that 99mTc-EDHT holds promising place for further optimization before nuclear medicine applications in different animal species.

Mapping of Translocator Protein (18 kDa) in Peripheral Sterile Inflammatory Disease and Cancer through PET Imaging.

Positron emission tomography (PET) imaging of the translocator 18 kDa protein (TSPO) with radioligands has become an effective means of research in peripheral inflammatory conditions that occur in many diseases and cancers. The peripheral sterile inflammatory diseases (PSIDs) are associated with a diverse group of disorders that comprises numerous enduring insults including the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system. TSPO has recently been introduced as a potential biomarker for peripheral sterile inflammatory diseases (PSIDs). The major critical issue related to PSIDs is its timely characterization and localization of inflammatory foci for proper therapy of patients. As an alternative to metabolic imaging, protein imaging expressed on immune cells after activation is of great importance. The five transmembrane domain translocator protein-18 kDa (TSPO) is upregulated on the mitochondrial cell surface of macrophages during inflammation, serving as a potential ligand for PET tracers. Additionally, the overexpressed TSPO protein has been positively correlated with various tumor malignancies. In view of the association of escalated TSPO expression in both disease conditions, it is an immensely important biomarker for PET imaging in oncology and PSIDs. In this review, we summarize the most outstanding advances on TSPO-targeted PSIDs and cancer in the development of TSPO ligands as a potential diagnostic tool, specifically discussing the last five years.

Lanthanide (Ln3+) complexes of bifunctional chelate: Synthesis, physicochemical study and interaction with human serum albumin (HSA).

Bifunctional chelate EDTA-bis amide (N,N'-bis (tyramide)ethylenediamine-N,N'-diacetic acid) that has ability to mimic natural amino acids was synthesized and analyzed by various spectroscopic techniques. The physicochemical studies were performed to calculate the various thermodynamic and kinetic parameters for the synthesized poly-amino carboxylate ligand. The two protonation constant (pka's = 3.460 and 6.722) of the prepared ligand and stability constants (log KML's = 15.8, 18.1, 16.2, 18.4, 17.5, 18.9, 13.6 and 12.8) of the complexes formed with Ce3+, Sm3+, Eu3+, Gd3+, Tb3+, Lu3+, Zn2+ and Cu2+ were determined by potentiometric titration using 0.1 M Me4NOH as non-aqueous base. The formation kinetics of [EuEDTA-TA2]+ and [CeEDTA-TA2]+ was studied and the rate constants were found to be 2.95 × 10-5 s-1 and 4.414 × 10-5 s-1respectively including the exchange reaction of [EuEDTA-TA2]+ with Zn2+ and Cu2+ spectrophotometrically. The Eu(III) complex of EDTA(TA)2 gives three emission bands at 480 nm, 540 nm and 610 nm (λmax = 270 nm, excitation) which shows efficacy of the ligand as an optical imaging agent. Molecular docking studies with Human Serum Albumin (HSA: PDB 1E78) showed binding pattern with the residues Arg218, Arg222, Lys195 and Lys444 in sub domain II A of site I via hydrogen bond and identifies the ligand-HSA interaction and specific insight for transportation to the target sites. Subsequently, fluorescence spectroscopy was performed at λex = 350 nm binding constant for HSA was 5.847 × 104 M-1 which showed effective quenching effect.

Modified benzoxazolone (ABO-AA) based single photon emission computed tomography (SPECT) probes for 18 kDa translocator protein.

Acetamidobenzoxazolone (ABO) has been modified to ABO-AA, 2-(2-(5-bromo/chloro benzoxazolone)acetamide)-3-(1H-indol-3-yl)propionate to improve pharmacokinetics and lipophilicity (log p = 2.04). The final compound was synthesized in better yield and in fewer steps than previously reported MBIP-Br (70% vs. 62%). Computational docking confirmed binding of MBIP-Cl with translocator protein (TSPO) as well as with mutant TSPO (-8.99 for PDB: 4RYQ and -9.30 for PDB: 4UC1, respectively). Ex-vivo biodistribution and scintigraphy showed that 99m Tc-MBIP-Cl is better than 99m Tc-MBIP-Br in terms of uptake in TSPO-rich organs and release kinetics 0-120 min postinjection. At 15 min, uptake was 2.75-fold (12.91%ID/g vs. 4.69%ID/g) in lung and seven-fold (5.16%ID/g vs. 0.72%ID/g) in heart for 99m Tc-MBIP-Cl compared to that of 99m Tc-MBIP-Br which gives warrant to utilize this single photon emission computed tomography agent in higher animals.

Enhanced Visualization of Latent Fingermarks on Rough Aluminum Surfaces Using Sequential Au and Zn/ZnS/ZnO Depositions.

Detection and visualization of fingermarks on rough and diffuse surfaces is a relatively challenging task. We succeeded in developing latent fingermarks on scratched and rough aluminum surfaces by sequential deposition of a thin layer of gold followed by one of zinc or zinc-based compounds on the fingermarks. The best image enhancement was achieved with sequential Au and ZnS depositions. Using this combination, we could enhance the visualization of latent fingermarks aged over 65 days in normal conditions. The optical reflectance from the fingermarks with the deposited layers of metal/dielectric is analyzed as a stratified medium. Significant contrast in the reflectance from the regions of the ridges and the valleys of the fingermark would enhance the visualization. Our results show that the Au and ZnS bi-layer combination can have a large reflection contrast and improved fingermark visualization at wavelengths corresponding to the green light for specific thickness of ZnS.

Block Copolymer Based Nanoparticles for Theranostic Intervention of Cervical Cancer: Synthesis, Pharmacokinetics, and in Vitro/in Vivo Evaluation in HeLa Xenograft Models.

Polymer-based nanoparticles have proven to be viable carriers of therapeutic agents. In this study, we have developed nanoparticles (NPs) from polypeptide-polyethylene glycol based triblock and diblock copolymers. The synthesized block copolymers poly(ethylene glycol)-b-poly(glutamic acid)-b-poly(ethylene glycol) (GEG) and poly(ethylene glycol)-b-poly(glutamic acid) (EG) conjugated with folic acid for targeting specificity (EGFA) have been used to encapsulate methotrexate (MTX) to form M-GEG and M-EGFA NPs aimed at passive and active targeting of cervical carcinoma. In-vitro SRB cytotoxicity and hemolysis assays revealed that these NPs were cytocompatible to healthy human cells and hemocompatible to human RBCs. Cellular uptake by FACS demonstrated their prompt internalization by human cervical carcinoma (HeLa) cells and points toward an apoptotic mechanism of cell kill as confirmed by AO/EB staining as well as histological analysis of explanted HeLa tumors. Pharmacokinetics and biodistribution studies were performed in New Zealand albino rabbits and HeLa xenografted Athymic mice models, respectively, by radiolabeling these NPs with 99mTc. Passive tumor accumulation and active targeting of MTX-loaded polymeric nanoparticles to folate expressing cells were confirmed by intravenous administration of these 99mTc-labeled M-GEG and M-EGFA NPs in HeLa tumor bearing nude mice and clearly visualized by whole-body gamma-SPECT images of these mice. Survival studies of these xenografted mice established the antiproliferative effect of these MTX-loaded NPs while corroborating the targeting effect of folic acid. These studies proved that the M-GEG NPs and M-EGFA NPs could be effective alternatives to conventional chemotherapy along with simultaneous diagnostic abilities and thus potentially viable theranostic options for human cervical carcinoma.

Studies for development of novel quinazolinones: new biomarker for EGFR.

The binding capabilities of a series of novel quinazolinone molecules were established and stated in a comprehensive computational methodology as well as by in vitro analysis. The main focus of this work was to achieve more insight of the interactions with crystal structure of PDB ID: 1M17 and predict their binding mode to EGFR. Three molecules were screened for further examination, which were synthesized and characterized using spectroscopic techniques. The persuasive affinity of these molecules towards EGFR inhibition (IC50 for QT=45nM) was established and validated from specific kinase assay including the cell viability spectrophotometric assay (QT=12nM). Drug likeliness property were also considered by analysing, the ADME of these molecules by using scintigraphic techniques. The result showed antitumour activity of QT (4.17 tumour/muscle at 4h). Further photo physical properties were also analysed to see in vitro HSA binding to QT.

Random lasing over gap states from a quasi-one-dimensional amplifying periodic-on-average random superlattice.

We report the experimental implementation and theoretical analysis of a random laser system that constitutes an amplifying periodic-on-average random superlattice (PARS). The stringent conditions on monodispersity required for a periodic-on-average random superlattice system are fulfilled using a linear array of spherical microresonators whose separation and size distribution can be controlled. Statistical studies of the lasing frequency reveal a frequency-controlled behavior. We perform transfer matrix calculations with gain to analyze the origin of the lasing modes, their thresholds, and frequency statistics. The results confirm that the experimentally observed lasing modes arise from states introduced into the stop gap of the underlying periodic system. On virtue of the fact that these high-quality gap states are restricted to a band of frequencies, the consequent random lasing exhibits significant reduction in frequency fluctuations.

Aerosol-based coherent random laser.

We demonstrate coherent random lasing from an aerosol of dye-doped microdroplets in air. The aerosol is in the form of a linear array of polydisperse, arbitrarily shaped, and randomly spaced microdroplets with average dimensions of about 30 µm. Upon optical excitation, ultranarrow lasing modes were observed in the emission along the axis of the linear array, while the transverse emission exhibited intrascatterer resonance peaks. Direct spatiospectral imaging and lasing threshold studies confirmed the origin of the lasing peaks to be from spatial modes that extended over the array of the polydisperse microdroplets.

Collective lasing from a linear array of dielectric microspheres with gain.

We experimentally study the optical emission behavior of a linear array of dielectric microspheres with gain. The microspheres are randomly arranged and well-separated, and can only couple via radiative modes. We observe resolution-limited, ultra-narrowband modes in the longitudinal emission, which constitutes collective lasing from the entire array, inferred from the observation of a lasing threshold. The lasing modes show wavelength selectivity, wherein the lasing probability is large only in specific frequency bands while being inhibited at other wavelengths, a behavior which is independent of the degree of configurational randomness. Analysis of the frequency bands indicates the participation of Fabry-Perot resonances of the individual microspheres in the collective emission.