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.

Nanoapatite-Loaded κ-Carrageenan/Poly(vinyl alcohol)-Based Injectable Cryogel for Hemostasis and Wound Healing.

Immediate control of excessive bleeding and prevention of infections are of utmost importance in the management of wounds. Cryogels have emerged as promising materials for the rapid release of medication and achieving hemostasis. However, their quick release properties pose the challenge of exposing patients to high concentrations of drugs. In this study, hybrid nanocomposites were developed to address this issue by combining poly(vinyl alcohol) and κ-carrageenan with whitlockite nanoapatite (WNA) particles and ciprofloxacin, aiming to achieve rapid hemostasis and sustained antibacterial effects. A physically cross-linked cryogel was obtained by subjecting a blend of poly(vinyl alcohol) and κ-carrageenan to successive freezing-thawing cycles, followed by the addition of WNA. Furthermore, ciprofloxacin was introduced into the cryogel matrix for subsequent evaluation of its wound healing properties. The resulting gel system exhibited a 3D microporous structure and demonstrated excellent swelling, low cytotoxicity, and outstanding mechanical properties. These characteristics were evaluated through analytical and rheological experiments. The nanocomposite cryogel with 4% whitlockite showed extended drug release of 71.21 ± 3.5% over 21 days and antibacterial activity with a considerable growth inhibition zone (4.19 ± 3.55 cm). Experiments on a rat model demonstrated a rapid hemostasis property of cryogels within an average of 83 ± 4 s and accelerated the process of wound healing with 96.34% contraction compared to the standard, which exhibited only ∼78% after 14 days. The histopathological analysis revealed that the process of epidermal re-epithelialization took around 14 days following the skin incision. The cryogel loaded with WNAs and ciprofloxacin holds great potential for strategic utilization in wound management applications as an effective material for hemostasis and anti-infection purposes.

A tuning fork-shaped bisbenzothiazole derivative as a pH-responsive digital fluorescent probe and its ex vivo evaluation.

A new highly emissive pH-responsive near-IR active digital probe was designed and synthesized. The probe is based on a bisbenzothiazole motif with a highly vulnerable hydrogen unit attached in an intramolecular fashion. The probe produced a large Stokes shift which was observed to be highly pH dependent. The optical pH dependence can be used for sensing pH over a wide range.

Multispectroscopic studies of binding interaction of phosmet with bovine hemoglobin.

Phosmet is a phthalimide derived broad spectrum organophosphate pesticide which is vastly used across the globe to protect several ornamental or horticulture crops. The toxicity of phosmet is of utmost concern because of its direct effect on the nervous system of the victim after exposure. The mechanism of phosmet toxicity was explored by the interaction with the model blood protein which is hemoglobin. Bovine Hemoglobin (BHb) is a major protein of red blood cells (RBCs) that plays an important role in the exchange of gases for respiration and ensures adequate oxygen supply to tissues for oxygenation. In the current study, the interaction of BHb with phosmet was revealed using various spectroscopic techniques. Circular dichroism (CD) and Fourier transform infrared spectroscopy (FTIR) studies of BHb in the presence of phosmet showed secondary structural changes in the protein post binding, Fluorescence study shows the involvement of the dynamic quenching predominantly, Van't Hoffs thermodynamic study showed negative enthalpy value and free energy change and negative entropy change that revealed the involvement of hydrogen bonding and van der Waal forces predominantly further revealing spontaneous nature of binding interaction. The shift in Ultraviolet-visible spectra also revealed the nature of the interaction. In-silico study finally deduced the involvement of hydrogen bonding and polar interaction. The study inferred the moderate interaction of BHb with phosmet.

Current advancement in the development of manganese complexes as magnetic resonance imaging probes.

Emerging non-invasive molecular imaging modalities can detect a pathophysiological state at the molecular level before any anatomic changes are observed. Magnetic resonance imaging (MRI) is preferred over other nuclear imaging techniques owing to its radiation-free approach. Conventionally, most MRI contrast agents employed predominantly involve lanthanide metal: Gadolinium (Gd) until the discovery of associated severe nephrogenic toxicity issues. This limitation led a way to the development of manganese-based contrast agents which offer similar positive contrast enhancement capability. A vast quantity of experimental data has been accumulated over the last decade to define the physicochemical characteristics of manganese chelates with various ligand scaffolds. One can now observe how the ligand configurations, rigidity, and donor-acceptor characteristics impact the stability of the complex. This review covers the current trends in the development of manganese-based MRI contrast agents, the mechanisms they are based on and design considerations for newer manganese-based contrast agents with higher diagnostic strength along with better safety profiles.

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.

Organosulphur and organoselenium compounds as emerging building blocks for catalytic systems for O-arylation of phenols, a C-O coupling reaction.

Diaryl ethers form an important class of organic compounds. The classic copper-mediated Ullmann diaryl ether synthesis has been known for many years and involves the coupling of phenols with aryl halides. However, the use of high reaction temperature, high catalyst loading and expensive ligands has created a need for the development of alternative catalytic systems. In the recent past, organosulphur and organoselenium compounds have been used as building blocks for developing homogeneous, heterogeneous and nanocatalysts for this C-O coupling reaction. Homogeneous catalytic systems include preformed complexes of metals with organosulphur and organoselenium ligands. The performance of such complexes is influenced dramatically by the nature of the chalcogen (S or Se) donor site of the ligand. Nanocatalytic systems (including Pd17Se15, Pd16S7 and Cu1.8S) have been designed using a single-source precursor route. Heterogeneous catalytic systems contain either metal (Cu or Pd) or metal chalcogenides (Pd17Se15 or Cu1.8S) as catalytically active species. This article aims to cover the simple and straightforward methodologies and approaches that are adopted for developing catalytically relevant organosulfur and organoselenium ligands, their homogeneous metal complexes, heterogeneous and nanocatalysts. The effects of chalcogen (S or Se) donor, halogen (Cl/Br/I) of aryl halide, nature (electron withdrawing or electron donating) of substituents present on the aromatic ring of aryl halides or substituted phenols and position (ortho or para) of substitution on the results of catalytic reactions have been critically analyzed and summarized. The effect of composition (Pd17Se15 or Pd16S7) on the performance of nanocatalytic systems is also highlighted. Substrate scope has also been discussed in all three types of catalysis. The superiority of heterogeneous catalytic systems (e.g., Pd17Se15 immobilised on graphene oxide) indicates the bright future possibilities for the development of efficient catalytic systems using similar or tailored ligands for this reaction.

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.

68Ga-Labeled bismacrocyclic methylene phosphonate as potential bone seeking PET radiopharmaceutical.

Phosphonates-based agents are well-known bone-seeking radiopharmaceuticals with application in detection and therapy. With higher sensitivity and resolution offered by Positron Emission Tomography (PET), tracers based on this technique are gaining huge attention. 68Ga-based generator and radiotracers render independence from the on-site cyclotron. We report the development of 68Ga-labeled DOTA-based bismacrocyclic phosphonate derivative, for bone PET imaging. The synthesis and characterization of 68Ga- DO3P-AME-DO3P was carried out in > 95% purity. The radiotracer displayed high stability and low binding affinity (<3%) to blood serum. High in vitro binding affinity were observed for synthetic hydroxyapatite, SAOS-2, osteoclast and osteoblast cells. In vivo pharmacokinetics revealed fast washout with biphasic release pattern. The deposition of radiotracer in osseous tissues was high (Bone/Muscle ratio:18), as studied from the biodistribution studies. In vivo PET/CT and biodistribution analyses revealed the ability of 68Ga-DO3P-AME-DO3P to target and accumulate in bone, thus displaying its potential as a PET bone imaging agent.

Chalcone Based Homodimeric PET Agent, 11C-(Chal)2DEA-Me, for Beta Amyloid Imaging: Synthesis and Bioevaluation.

Homodimeric chalcone based 11C-PET radiotracer, 11C-(Chal)2DEA-Me, was synthesized, and binding affinity toward beta amyloid (Aß) was evaluated. The computational studies revealed multiple binding of the tracer at the recognition sites of Aß fibrils. The bivalent ligand 11C-(Chal)2DEA-Me displayed higher binding affinity compared to the corresponding monomer, 11C-Chal-Me, and classical Aß agents. The radiolabeling yield with carbon-11 was 40-55% (decay corrected) with specific activity of 65-90 GBq/µmol. A significant ( p < 0.0001) improvement in the binding affinity of 11C-(Chal)2DEA-Me with synthetic Aß42 aggregates over the monomer, 11C-Chal-Me, demonstrates the utility of the bivalent approach. The PET imaging and biodistribution data displayed suitable brain pharmacokinetics of both ligands with higher brain uptake in the case of the bivalent ligand. Metabolite analysis of healthy ddY mouse brain homogenates exhibited high stability of the radiotracers in the brain with >93% intact tracer at 30 min post injection. Both chalcone derivatives were fluorescent in nature and demonstrated significant changes in the emission properties after binding with Aß42. The preliminary analysis indicates high potential of 11C-(Chal)2DEA-Me as in vivo Aß42 imaging tracer and highlights the significance of the bivalent approach to achieve a higher biological response for detection of early stages of amyloidosis.

Can 18F-Fluoroestradiol Positron Emission Tomography Become a New Imaging Standard in the Estrogen Receptor-positive Breast Cancer Patient: A Prospective Comparative Study with 18F-Fluorodeoxyglucose Positron Emission Tomography?

Correct staging is the most crucial for the treatment outcome in cancer management. Molecular imaging with 18F-fluoroestradiol (FES) positron emission tomography-computed tomography (PET-CT) targets estrogen receptor (ER) and may have a higher incremental value in diagnosis by aiding specificity. We enrolled 12 female breast cancer patients prospectively and did 18F-FES PET-CT and 18F-fluorodeoxyglucose (FDG) PET-CT within 1 week interval time. Lesion detection sensitivity was compared for a total number of lesions and for nonhepatic lesions only by McNemar test. 18F-FES PET-CT was taken as reference in case of indeterminate lesions. The incremental value reported by identifying 18F-FES exclusive lesions and by characterization of 18F-FDG indeterminate lesions. Spearman rank test was used to correlate ER expression and maximum standardized uptake value (SUVmax). Two ER-negative patients with no 18F-FES uptake were excluded. Ten ER-positive patients with 154 disease lesions were finally analyzed. 18F-FDG picked-up 142 lesions (sensitivity 92.21%), whereas 18F-FES picked-up 116 lesions (sensitivity 75.32%) and this difference was statistically significant. For nonhepatic lesions (n = 136) detectability, 18F-FDG picked-up 124 (sensitivity 91.18%), whereas 18F-FES picked-up 116 (sensitivity 85.29%) lesions and this difference was not statistically significant. Beside 12 exclusive lesions, 18F-FES characterized 41 (27.5%) 18F-FDG indeterminate lesions. Overall 18F-FES impacted 20% patient management. The positive trend was also seen with 18F-FES SUVmax with ER expression and negative with 18F-FDG SUVmax. We conclude, 18F-FDG has overall better sensitivity than 18F-FES PET-CT, however for nonhepatic metastasis difference was not significant. 18F-FES PET-CT better-characterized lesions and impacted 20% patient management. Therefore, 18F-FES PET-CT should be used with 18F-FDG PET-CT in strongly ER expressing patients for better specificity.

Zinc complex of tryptophan appended 1,4,7,10-tetraazacyclododecane as potential anticancer agent: Synthesis and evaluation.

With the rising incidences of cancer cases, the quest for new metal based anticancer drugs has led to extensive research in cancer biology. Zinc complexes of amino acid residue side chains are well recognized for hydrolysis of phosphodiester bond in DNA at faster rate. In the presented work, a Zn(II) complex of cyclen substituted with two l-tryptophan units, Zn(II)-Cyclen-(Trp)2 has been synthesized and evaluated for antiproliferative activity. Zn(II)-Cyclen-(Trp)2 was synthesized in ∼70% yield and its DNA binding potential was evaluated through QM/MM study which suggested good binding (G=-9.426) with B-DNA. The decrease in intensity of the positive and negative bands of CT-DNA at 278nm and 240nm, respectively demonstrated an effective unwinding of the DNA helix with loss of helicity. The complex was identified as an antiproliferative agent against U-87MG cells with 5 fold increase in apoptosis with respect to control (2h post incubation, IC50 25µM). Electrophoresis and comet assay studies exhibited an increase in DNA breakage after treatment with complex while caspase-3/ß-actin cleavage established a caspase-3 dependent apoptosis pathway in U-87 MG cells after triggering DNA damage. In vivo tumor specificity of the developed ligand was validated after radiocomplexation with 99mTc (>98% radiochemical yield and specific activity of 2.56GBq/µmol). Avid tumor/muscle ratio of >6 was depicted in biodistribution and SPECT imaging studies in U-87 MG xenograft model nude mice.

Bivalent Approach for Homodimeric Estradiol Based Ligand: Synthesis and Evaluation for Targeted Theranosis of ER(+) Breast Carcinomas.

The synthesis of estradiol based bivalent ligand [(EST)2DT] is reported and its potential for targeted imaging and therapy of ER(+) tumors has been evaluated. For the purpose, ethinylestradiol was functionalized with an azidoethylamine moiety via click chemistry. The resultant derivative was reacted in a bivalent mode with DTPA-dianhydride to form the multicoordinate chelating agent, (EST)2DT which displayed capability to bind (99m)Tc. The radiolabeled complex, (99m)Tc-(EST)2DT was obtained in >99% radiochemical purity and 20-48 GBq/µmol of specific activity. RBA assay revealed ∼15% binding with estrogen receptor. Evaluation of ligand on ER(+)-cell line (MCF-7) suggested enhanced and ER-mediated uptake. In vivo assays displayed early tracer accumulation in MCF-7 xenografts with tumor to muscle ratio ∼6 in 2 h and negligible uptakes in nontargeted organs. MTT assay performed on ER(+) and ER(-) cell lines displayed selective inhibition of ER(+) cancer cell growth with IC50 = 14.3 µM which was comparable to tamoxifen. The anticancer activity of the ligand is possibly due to the increase in ERß and suppression of ERα protein levels in gene transcription. The studies reveal the potential of (EST)2DT as diagnostic imaging agent with the additional benefits in therapy.

Metal based imaging probes of DO3A-Act-Met for LAT1 mediated methionine specific tumors: synthesis and preclinical evaluation.

PURPOSE: Tumor cells are known to have an elevated requirement for methionine due to increased protein synthesis and trans-methylation reactions. A methionine based macrocyclic tumor imaging system, DO3A-Act-Met, has been designed to provide a novel platform for tumor imaging via modalities, PET/MRI using metal ions, (68)Ga and (157)Gd. METHODS: Synthesis of DO3A-Act-Met was confirmed through NMR and mass spectrometric techniques. Cytotoxicity of complexes was evaluated using MTT assay whereas receptor binding and trans-stimulation studies were performed on EAT and U-87 MG cell lines. Tumor targeting was assessed through imaging and biodistribution experiments on U-87 MG xenograft model. RESULTS: DO3A-Act-Met was synthesized and radiolabeled with (68)Ga in high radiochemical purity (85-92%). The receptor binding assay on EAT cells predicted high binding affinity with Kd of 0.78 nM. Efflux of (35)S-L-methionine trans-stimulated by extracellular DO3A-Act-Met on U-87MG cells suggested an L-system transport. MR studies revealed a longitudinal relaxivity of 4.35 mM(-1) s(-1) for Gd-DO3A-Act-Met and a 25% signal enhancement at tumor site. The biodistribution studies in U-87MG xenografts validated tumor specificity. CONCLUSION: DO3A-Act-Met, a methionine conjugated probe is a promising agent for targeted molecular imaging, exhibiting high specificity towards tumor owing to its essential role in proliferation of cancer cells mediated through LAT1.

(68)Ga based probe for Alzheimer's disease: synthesis and preclinical evaluation of homodimeric chalcone in ß-amyloid imaging.

In an attempt to explore use of PET radioisotope, (68)Ga, in the diagnosis of Alzheimer's disease, a metal-based homodimeric ligand exhibiting high affinity towards Aß aggregates was designed by conjugating two chalcone units with the chelating system, diethylenetriaminepentaacetic acid. Bischalcone derivative, 5,8-bis(carboxymethyl)-13-(4-((E)-3-(4-(dimethylamino)phenyl)acryloyl)phenoxy)-2-(2-(2-(4-((E)-3-(4-(dimethylamino)phenyl)acryloyl)phenoxy)ethylamino)-2-oxoethyl)-10-oxo-2,5,8,11-tetraazatridecane-1-carboxylic acid, DT(Ch)2 was synthesized in 95% yield with high purity. It was radiolabelled with (68)Ga under mild conditions with 85.4% efficiency and 9.5-10 MBq nmol(-1) specific activity. An in vitro binding assay on Aß42 aggregates displayed high binding affinity of (68)Ga-DT(Ch)2 and inhibition constant of 4.18 ± 0.62 nM. The fluorescent properties of the ligand with peaks of absorption/emission at 410/540 nm exhibited a blue shift with 5.5-fold increase in emission intensity on binding with Aß aggregates. Blood kinetics of the complex performed on normal rabbit exhibited fast clearance (t1/2(F) = 24 ± 0.08 min; t1/2(S) = 2 h 40 ± 0.04 min). Ex vivo biodistribution analysis demonstrated blood-brain barrier penetration with brain uptake of 1.24 ± 0.31% ID g(-1) at 2 min p.i. and rapid washout with negligible activity (0.36% ID g(-1)) left at 30 min p.i. These preliminary studies reveal that the bivalent approach of synthesis had minimal effect on binding affinity, signifying that the developed (68)Ga-complex, (68)Ga-DT(Ch)2, may offer a new perspective in generator produced PET imaging probes for Alzheimer's disease.

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.

Preclinical evaluation of DO3A-Act-AQ: a polyazamacrocyclic monomeric anthraquinone derivative as a theranostic agent.

An anthraquinone conjugated macrocyclic chelating agent, 2,2',2″-(10-(2-(9,10-dioxo-9,10-dihydroanthracen-1-ylamino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid or DO3A-Act-AQ, was synthesized by reacting trisubstituted cyclen (DO3A) with 2-chloro-N-(9,10-dioxo-9,10-dihydro-anthracen-1-yl)-acetamide and radiolabeled with (68)GaCl3 in 84% efficiency and a specific activity of 4.62 MBq/nmol. The IC50 value for BMG-1 cells was 0.1 mM, while the same concentration of DO3A-Act-AQ rendered no significant toxicity in HEK cells. The exposure of BMG-1 cells with 0.1 mM DO3A-Act-AQ displayed a time-dependent increase in apoptosis (40.7% at 4 h and 53% at 24 h), and the effect was 2.8- and 3.6-fold % higher as seen in HEK cells. An increase in S-phase cell population suggested S-phase arrest concomitant with induction of apoptosis in BMG-1 cells reaching to 4.5 times after 24 h with respect to control cells. DNA binding studies on CT-DNA (calf thymus) revealed a quenching pattern in the presence of DO3A-Act-AQ (10-70 µM), and the Stern-Volmer quenching constant was 2.4157 × 10(6) L mol(-1), indicative of strong binding with ds-DNA. A decrease in the positive and negative bands of CT-DNA was seen at 278 nm and 240 nm, respectively, on addition of 0.05 mM of DO3A-Act-AQ in CD studies. (68)Ga-DO3A-Act-AQ was stable in vitro in both PBS and human serum for at least 2 h. The in vivo blood kinetics study performed on normal rabbits indicated fast clearance with t1/2(F) = 40 ± 0.3 min and t1/2(S) = 3 h 30 min ± 0.1 min. Ex vivo biodistribution analysis displayed a favorable tumor-to-muscle ratio of 8.4 after 2 h in athymic nude mice xenografted with BMG-1 cells, suggesting the specificity of (68)Ga-DO3A-Act-AQ toward tumors.

Design and docking studies of [diethylenetriaminepentaacetic acid-(amino acid)2] with acetylcholine receptor as a molecular imaging agent for single-photon emission computed tomographic application.

The acetylcholine receptor is an essential link between the brain and the muscles, so it is a sensitive location for attack. In this study, some reversible [diethylenetriaminepentaacetic acid-(amino acid)2] have been docked computationally to the active site of the acetylcholine receptor. The induced fit method was employed to perform the automolecular docking for these systems. The result of docking studies generated thermodynamic properties, such as free energy of bindings (Glide score) and their weak electrostatic interactions. On the basis of these results, scintigraphic imaging studies were performed in mice. Among the radiotracers evaluated in this study, compound derived from 5-hydroxytryptophan/tryptophan exhibited remarkable localization in the brain, whereas radiotracer derived from l-histidine shows moderate accumulation in the brain. Preliminary studies with these amino acid-based ligands are encouraging to carrying out further in vivo experiments for targeted imaging.

Design, synthesis, and antimycobacterial property of PEG-bis(INH) conjugates.

Poly(ethylene glycol) derivatives of isoniazid with varying molecular weight of poly(ethylene glycol) were designed as antimycobacterial agents. Poly(ethylene glycol)-diacrylate of three different molecular weights (MW 258, 575, and 700) was conjugated with isoniazid by the Michael addition approach. The poly(ethylene glycol)-bis(isoniazid) conjugates thus obtained were completely characterized by FT-IR, (1)H and (13)C NMR, and ESI-MS spectroscopic techniques. Comparative MTT assay of the poly(ethylene glycol)-bis(isoniazid) conjugates showed much lower cytotoxicity than the neat isoniazid. MIC studies on Mycobaterium tuberculosis H37Rv showed potential antimycobacterial activity than the free isoniazid on a molar basis. The poly(ethylene glycol)-bis(isoniazid) conjugates were successfully radiolabeled with 99m-Technetium with more than 97% efficiency and stability to assess their in vivo fate. The (99m)Tc labeled poly(ethylene glycol)-bis(isoniazid) conjugates showed higher blood retention time in New Zealand rabbits which increased with increasing molecular weight of poly(ethylene glycol). Biodistribution studies in infection-induced murine models (BALB/c mice) showed significant retention of these conjugates at the site of infection for 72 h. The results of this study illustrate the potential utility of the PEGylated isoniazid conjugates as long circulating carriers for improved antitubercular drug therapy.

Correlation of physical parameters during radiochemical synthesis of (18)F positron emission tomography radiopharmaceuticals.

Positron emission tomography is a highly specialized imaging technique using short-lived radiolabel substances to produce extremely high resolution images of the body's biological function. The (18)F(-) ion is produced via the (18)O(p,n)(18)F reaction using a silver target cell filled with 1.4 mL of enriched [(18)O] water. On a typical run, the target is irradiated for 45 minutes with 16.5 MeV protons (on target) and an average beam current of 5-45 mA. When the same reaction takes place with [(16)O] water [(13)N] Ammonia is produced as the primary product by the abstraction of hydrogen from water. This study investigated the physical parameters of medical cyclotron during the radiochemical process with induced radioactivity flux and mutual correlation of physical parameters for 16.5 MeV medical cyclotron at the INMAS Delhi, India. It is observed that by getting farther from the target, the relative number of low-energy neutrons increases while the overall flux of neutrons decreases. This is due to multiple scattering of high-energy neutrons in the walls and eventually absorption of low-energy neutrons. The other parameters are also linked with each other which are correlatable.