Meganathan Thirumal

University of Delhi, Old Delhi, NCT, India

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Publications (6)20.01 Total impact

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    ABSTRACT: Bifunctional chelate, 6,6'-(2-aminoethylazanediyl)bis(methylene)dipicolinicacid (H2pentapa-en-NH2), has been synthesized and labeled with 99mTc with specific activity of 135−140 MBq/μmol in >95% yield. The in vitro stability of the labeled chelate in both PBS and human serum shows only <5% dissociation at 24 h. The in vivo distribution pattern of the labeled chelator in normal as well as EAT tumor bearing BALB/c mice suggested renal as the major route of excretion with <2% ID/g uptake in other organs. The target specificity of the chelate towards tumor was introduced by conjugating two molecules of methionine. The conjugated H2pentapa-en-met2 was synthesized in >85% yield and labeled with 99mTc in 96.2% radiochemical yield with specific activity of 110−125 MBq/μmol. The conjugate probe exhibited high serum stability (>94% at 24 h). The in vivo blood kinetic studies of radiocomplexes of H2pentapa-en-NH2 and its methionine conjugated derivative exhibited fast clearance with t1/2(F) = 32 ± 0.14 min, t1/2(S) = 4 h 20 min ± 0.21 min and t1/2(F) = 27 ± 0.3 min, t1/2(S) = 4 h 01 min ± 0.11 min, respectively. In vivo scintigraphy and ex vivo biodistribution studies in EAT tumor bearing mice demonstrated high retention of H2pentapa-en-met2 at the site of tumor with tumor to muscle ratio of 6.52 at 1 h, indicating the high specificity of 99mTc-pentapa-en-met2 toward tumors.
    RSC Advances 01/2015; 5(43):33963-33973. DOI:10.1039/C4RA13690J · 3.71 Impact Factor
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    ABSTRACT: 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, 68Ga and 157Gd. 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 68Ga 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 35S-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.
    Pharmaceutical Research 08/2014; 32(3). DOI:10.1007/s11095-014-1509-x · 3.95 Impact Factor
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    ABSTRACT: 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.
    European Journal of Medicinal Chemistry 05/2014; 82C:225-232. DOI:10.1016/j.ejmech.2014.05.046 · 3.43 Impact Factor
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    ABSTRACT: Herein, an efficient synthetic approach to a furopyrazine scaffold with four points of diversity, starting from 2(1H)-pyrazinones, with dipeptomimetic properties, is presented. R-groups corresponding to amino acid side chains were introduced during the 2(1H)-pyrazinone and subsequent furopyrazine formation. The furopyrazine scaffold was further functionalized with an amino- and a carboxy-terminus resulting in a conformationally restricted dipeptidomimetic scaffold. The carboxy-terminus was introduced via a chemoselective vinylation of the 7-position followed by oxidative cleavage, while the amino-terminus was obtained via Buchwald–Hartwig amidation of the 2-position of the scaffold. The versatility of the synthetic method was demonstrated by the synthesis of a small library of diversely substituted furopyrazines having various amino acid side chains on the four points of diversity. Evaluation with an X-ray structure of the scaffold and computational analysis supports the exploitation of the furopyrazine scaffold as a restricted dipeptide mimic, which can mimic the two central residues of a β-turn.
    ChemInform 04/2012; 68(14):3019–3029. DOI:10.1016/j.tet.2012.02.022
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    ABSTRACT: 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).
    Dalton Transactions 02/2011; 40(13):3346-51. DOI:10.1039/c0dt01370f · 4.10 Impact Factor
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    ABSTRACT: A phosphonate derivative 10'-bis(acetamido)-ethane-bis[1,4,7-tri(methylene phosphonic acid)-1,4,7,10-tetraazacyclododecane] (DO3P-AME-DO3P), was synthesized with 90% yield in high purity. It was labeled with (99m)Tc in 97.5% efficiency and specific activity of 112-250 MBq/μmol. The binding affinity of (99m)Tc-DO3P-AME-DO3P towards bone minerals was tested in vitro by using hydroxy apatite as a bone model with absorption of 93% during the first hour of the experiment. Receptor binding assay on human bone cell line SAOS-2 demonstrated K(d) value of 1.07 nM. Cell binding studies of DO3P-AME-DO3P on osteoblasts and osteoclasts cells performed in vitro displayed preferential affinity of the compound towards osteoclast (167.95 ± 3.56% dose/mg protein). The serum stability of (99m)Tc complex was found to be 96.8% after 24 h. Blood kinetics of (99m)Tc-DO3P-AME-DO3P performed on normal rabbits showed fast clearance with t(1/2)(F) = 15 min ± 0.014 min and t(1/2)(S) = 4 h 3 min ± 0.09 min. Biodistribution studies carried out in normal BALB/c mice showed bone-to-blood ratio of 20 and bone-to-muscle ratio of 33. The bone tissue demonstrated highest concentration of bound radioactivity with 10.73% ID/g at 1 h post injection. The protonation and stability constants were determined by pH-potentiometry titrations. The stability constants of DO3P-AME-DO3P with Lu(III), Sm(III), and Ho(III) were 19.7, 21.8, and 20.2 determined by "out of cell" method. The excellent bone seeking properties of DO3P-AME-DO3P make it a candidate of choice for SPECT imaging and preferential uptake of the compound in osteoclasts in comparison to osteoblasts; BMM and BMC can be used to understand the pathway of pathogenesis of osteoporosis and skeletal metastases.
    Bioconjugate Chemistry 02/2011; 22(2):244-55. DOI:10.1021/bc100382c · 4.82 Impact Factor