Pre-clinical evaluation of 99mTc-labeled chalcone derivative for amyloid-ß imaging post-head trauma.

Aß42 plaque formation is one of the preliminary pathologic events that occur post traumatic brain injury (TBI) which is also among the most noteworthy hallmarks of AD. Their pre symptomatic detection is therefore vital for better disease management. Chalcone-picolinic acid chelator derivative, 6-({[(6-carboxypyridin-2-yl)methyl](2-{4-[(2E)-3-[4-(dimethyl amino)phenyl]prop-2-enoyl]phenoxy}ethyl)amino}methyl)pyridine-2-carboxylic acid, Py-chal was synthesized to selectively identify amyloid plaques formed post head trauma using SPECT imaging by stable complexation to 99mTc with > 97% efficiency without compromising amyloid specificity. The binding potential of the Py-chal ligand to amyloid plaques remained high as confirmed by in vitro binding assay and photophysical spectra. Further, the Py-chal complex stained amyloid aggregates in the brain sections of rmTBI mice model. In vivo scintigraphy in TBI mice model displayed high uptake followed by high retention while the healthy rabbits displayed higher brain uptake followed by a rapid washout attributed to absence of amyloid plaques. Higher uptake in brain of TBI model was also confirmed by ex vivo biodistribution analysis wherein brain uptake of 3.38 ± 0.2% ID/g at 2 min p.i. was observed for TBI mice model. This was followed by prolonged retention and more than twofold higher activity as compared to sham mice brain. This preliminary data suggests the specificity of the radiotracer for amyloid detection post head trauma and applicability of 99mTc labeled Py-chal complex for TBI-induced ß-amyloid SPECT imaging.

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 Redox Properties of Superbenzene Porphyrin Conjugates.

Superbenzene porphyrin conjugates find wide range of applications from nonlinear optical materials to semiconductors. Herein, we report the synthesis and characterization of 5,15-bis(3,5-di-tert-butylphenyl)-10,20-bis(pentaphenylphenyl)phenylporphyrin and its Zinc-metallated complex. Oxidative planarization of 5,15-bis(3,5-di-tert-butylphenyl)-10,20-bis(pentaphenylphenyl)phenylporphyrin and its metallated complex was carried out by using NOBF4 as an oxidizing agent. The formation of superbenzene porphyrin conjugates validates its Scholl type reactions. The laboratory-synthesized porphyrin conjugates were characterized experimentally using spectroscopic techniques such as 1H NMR, 13C NMR, electron spin resonance, and ultraviolet-visible spectroscopy for structural conformation. In addition, density functional theory calculations were carried out to validate the experimental results. The theoretical and experimental results show that the 4-(pentaphenylphenyl)phenyl ligand increases the stability, optical properties, and rate of planarization of synthesized porphyrins. The conjugates exhibited intense and distant electronic communication between two hexabenzocoronene sites, taking advantage of porphyrin as a π-spacer. The π-radical cation has also been found to be an intermediate in oxidative C-C bond formation. NICS calculations support such a conclusion.

Phytochemical and biological review of Aegle marmelos Linn.

India has one of the most expanded plant-origin medical traditions in the world. Researchers have evaluated molecules obtained from plants to treat a variety of ailments. Literature review shows that fundamental parts of the plant are used to treat different diseases. The related data is retrieved from Google scholar, PubMed, Science Direct and Scopus. The keywords include Bael, A. marmelos, Vilvam, and Marmelosin. Extensive studies show that A. marmelos has antidiarrhoeal, antimicrobial, antiviral, anticancer, chemopreventive, antipyretic, ulcer healing, antigenotoxic, diuretic, antifertility, and anti-inflammatory properties. In this work, an updated literature review is presented to clarify the current state of research on A. marmelos elucidating its constituents and their most relevant biological activities.

India has one of the most expanded plant-origin medical traditions in the world. A. marmelos Linn, also familiar as bael, belongs to Rutaceae and is widely grown worldwide. A. marmelos is a fruit with various medicinal advantages. We searched various databases, studied elaborately, and understood the importance of this fruit. Thus, its constituents can help mitigate various diseases.

Bio-Evaluation of 99mTc-Labeled Homodimeric Chalcone Derivative as Amyloid-ß-Targeting Probe.

Chalcone derivatives have been successfully utilized for a range of biological applications and can cross the blood-brain barrier easily. ß-amyloid-specific bis-chalcone derivative, 6,9-bis(carboxymethyl)-14-(4-[(E)-3-(4-(dimethylamino)phenyl)acryloyl]phenoxy)-3-(2-[(2-(4-[(E)-3-(4-(dimethylamino)phenyl)acryloyl]phenoxy)ethyl)amino]-2-oxoethyl)-11-oxo-3,6,9,12-tetraazatetradecanoic acid, DT(Ch)2, was analyzed using molecular modeling to explain the binding modes of the ligand with amyloid fibril and monomer followed by 99mTc-complexation in 95% yield and 98.7% efficiency. High-binding specificity of the radiocomplex was established following in vitro evaluation against 100-fold excess of DT(Ch)2. 99mTc-DT(Ch)2 exhibited <3% trans-complexation in human serum after 24 h, indicating high stability. A fast clearance rate in pharmacokinetics studies displayed a biphasic pattern with t 1/2(F) = 30 min ± 0.09 and t 1/2(S) = 4 h 20 min ± 0.06. In vivo single-photon emission computed tomography (SPECT) imaging in rabbits reiterated the pharmacokinetics data with initially high brain uptake followed by rapid washout. Biodistribution studies confirmed the initial brain uptake as 1.16 ± 0.02% ID/g after 2 min and the brain2min/brain30min ratio was 3.74. Radioactivity distribution in the brain was >40% in the cingulate cortex followed by >25% in the hippocampus, a distribution pattern aligned to Alzheimer's affected brain regions. Radiocomplex also displayed rapid plasma clearance followed by hepatobolic and renal modes of excretion.

Synthesis and antimycobacterial activity of 1-(ß-d-Ribofuranosyl)-4-coumarinyloxymethyl- / -coumarinyl-1,2,3-triazole.

A series of ß-d-ribofuranosyl coumarinyl-1,2,3-triazoles have been synthesized by Cu-catalyzed cycloaddition reaction between azidosugar and 7-O-/7-alkynylated coumarins in 62-70% overall yields. The in vitro antimycobacterial activity evaluation of the synthesized triazolo-conjugates against Mycobacterium tuberculosis revealed that compounds were bactericidal in nature and some of them were found to be more active than one of the first line antimycobacterial drug ethambutol against sensitive reference strain H37Rv, and 7 to 420 times more active than all four first line antimycobacterial drugs (isoniazid, rifampicin, ethambutol and streptomycin) against multidrug resistant clinical isolate 591. Study of in silico pharmacokinetic profile indicated the drug like characters for the test molecules. Further, transmission electron microscopic experiments revealed that these compounds interfere with the constitution of bacterial cell wall possibly by targeting mycobacterial InhA and DNA gyrase enzymes. Study conducted on the activities of the test compounds on bacterial InhA and DNA gyrase revealed that the most bactericidal test compound, N1-(ß-d-ribofuranosyl)-C4-(4-methylcoumarin-7-oxymethyl)-1,2,3-triazole (6b) and its corresponding directly linked conjugate N1-(ß-d-ribofuranosyl)-C4-(4-methylcoumarin-7-yl)-1,2,3-triazole (11b) significantly inhibited the activity of both the enzymes. The results were further supported by molecular docking studies of the compound 6b and 11b with bacterial InhA and DNA gyrase B enzymes. Further, the cytotoxicity study of some of the better active compounds on THP-1 macrophage cell line using MTT assay showed that the synthesized compounds were non-cytotoxic.

Use of gentamicin impregnated POP discs for antibiotic pouch dressing.

Antibiotic pouch technique is commonly used due to the high local antibiotic concentration and moist environment for wound healing. We used locally made gentamicin impregnated Plaster of Paris discs in treating wounds with exposed deep structures like tendons and bones. Out of 22 patients treated with this method, 19 completed treatment. Granulation tissue formed quickly and effectively covered the exposed structures. All wounds either healed by secondary intention or became suitable for split skin grafting. Gentamicin impregnated Plaster of Paris disc pouch dressing is safe, cost saving, and effective for management of deep open wounds.

Bone transport in the management of fractures of the tibia.

A review was carried out in 21 cases of bone transport in the tibia done between May 1995 and December 1997. These were done for the treatment of compound (Grade IIIB) fractures with extensive bone and soft tissue loss and in infective non-unions of the tibia using the Ilizarov technique and ring fixator. In 5 cases, 2 or 3 additional procedures were needed such as tendo achilles (TA) lengthening, bone grafting, revision of construct or revision of scar at the docking site. Average resection of infected bone was 5.2 cms in the infective non-union group and average bone and soft tissue loss was 8 cms in the compound Grade IIIB fracture group. The defect was bridged and regenerate bone occurred in all the cases except one. Union was achieved in all the cases although 10 needed bone grafting. Infection was eradicated in all the cases. Limb length discrepancy was corrected in all the cases except three. Mean duration of treatment was 12 months.

Design and synthesis of calcium responsive magnetic resonance imaging agent: Its relaxation and luminescence studies.

Calcium concentration modulation both inside and outside cell is of considerable interest for nervous system function in normal and pathological conditions. MRI has potential for very high spatial resolution at molecular/cellular level. Design, synthesis and evaluation of Gd-DO3A-AME-NPHE, a calcium responsive MRI contrast agent is presented. The probe is comprised of a Gd(3+)-DO3A core coupled to iminoacetate coordinating groups for calcium induced relaxivity switching. In the absence of Ca(2+) ions, inner sphere water binding to the Gd-DO3A-AME-NPHE is restricted with longitudinal relaxivity, r1 = 4.37 mM(-1) s(-1) at 4.7 T. However, addition of Ca(2+) triggers a marked enhancement in r1 = 6.99 mM(-1) s(-1) at 4.7 T (60% increase). The construct is highly selective for Ca(2+) over competitive metal ions at extracellular concentration. The r1 is modulated by changes in the hydration number (0.2 to 1.05), which was confirmed by luminescence emission lifetimes of the analogous Eu(3+) complex. T1 phantom images establish the capability of complex of visualizing changes in [Ca(2+)] by MRI.

Facile synthesis of non-ionic dimeric molecular resonance imaging contrast agent: its relaxation and luminescence studies.

A bis-polyazamacrocycle, 10'-bis(acetamido)ethane-bis[1,4,7-tri(carboxymethane)-1,4,7,10-tetraazacyclododecane] (DO3A-AME-DO3A) was synthesized for application in magnetic resonance imaging. The efficacy of DO3A-AME-DO3A as non ionic magnetic contrast agent was tested by performing relaxometric studies on its gadolinium complex. The longitudinal relaxivity, r(1) and transverse relaxivity, r(2) values were found to be 5.84 mM(-1)s(-1) and 6.82 mM(-1)s(-1), per Gd(III) at pH 7.0, 37 °C. The luminescence properties of europium complex of DO3A-AME-DO3A were investigated in aqueous medium. The lifetime of Eu(2)-DO3A-AME-DO3A in water was found to be 0.786 ms. Emission and luminescence lifetime measurements on the europium complex of DO3A-AME-DO3A gives a hydration number of q = 1.9. The reaction enthalpy and entropy were found to be, ΔH(0) = -(6.2 ± 2) kJ mol(-1), ΔS(0) = - (1.8 ± 0.4) kJ mol(-1)K(-1), and K(Eu)(298) = (1.8 ± 0.1).