5-HT1A targeting PARCEST agent DO3AM-MPP with potential for receptor imaging: Synthesis, physico-chemical and MR studies

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5-HT1A targeting PARCEST agent DO3AM-MPP with potential for receptor imaging : Synthesis, physico-chemical and MR studies

Article/chapterEnglish2021

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Elsevier,2021
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LIBRIS-ID:oai:DiVA.org:uu-434438
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-434438URI
https://doi.org/10.1016/j.bioorg.2020.104487DOI

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Language:English
Summary in:English

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Contrast enhancement in MRI using magnetization or saturation transfer techniques promises better sensitivity, and faster acquisition compared to T-1 or T-2 contrast. This work reports the synthesis and evaluation of 5-HT1A targeted PARACEST MRI contrast agent using 1,4,7,10-tetraazacycloDOdecane-4,7,10-triacetAMide (DO3AM) as the bifunctional chelator, and 5-HT1A-antagonist methoxyphenyl piperazine (MPP) as a targeting unit. The multistep synthesis led to the MPP conjugated DO3AM with 60% yield. CEST-related physicochemical parameters were evaluated after loading DO3AM-MPP with paramagnetic MRI active lanthanides: Gadolinium (Gd-DO3AM-MPP) and Europium (Eu-DO3AM-MPP). Luminescence lifetime measurements with Eu-DO3AM-MPP and computational DFT studies using Gd-DO3AM-MPP revealed the coordination of one water molecule (q = 1.43) with metal-water distance (r(M)-H2O) of 2.7 angstrom and water residence time (tau(m)) of 0.23 ms. The dissociation constant of K-d 62 +/- 0.02 pM as evaluated from fluorescence quenching of 5-HT1A (protein) and docking score of -4.81 in theoretical evaluation reflect the binding potential of the complex Gd-DO3AM-MPP with the receptor 5-HT1A. Insights of the docked pose reflect the importance of NH2 (amide) and aromatic ring in Gd-DO3AM-MPP while interacting with Ser 374 and Phe 370 in the antagonist binding pocket of 5-HT1A. Gd-DO3AM-MPP shows longitudinal relaxivity 5.85 mM(-1)s(-1) with a water residence lifetime of 0.93 ms in hippocampal homogenate containing 5-HT1A. The potentiometric titration of DO3AM-MPP showed strong selectivity for Gd3+ over physiological metal ions such as Zn2+ and Cu2+. The in vitro and in vivo studies confirmed the minimal cytotoxicity and presential binding of Gd-DO3AM-MPP with 5-HT1A receptor in the hippocampus region of the mice. Summarizing, the complex Gd-DO3AM-MPP can have a potential for CEST imaging of 5-HT1A receptors.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Farmakologi och toxikologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Pharmacology and Toxicology hsv//eng
Chemical Exchange Saturation Transfer
Computational Studies
Density Functional Theory
Water Residence Lifetime
Longitudinal and Transverse relaxivity
Fluorescence quenching

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Chaturvedi, ShubhraDef Res & Dev Org, Div Cyclotron & Radiopharmaceut Sci, Inst Nucl Med & Allied Sci, Brig SK Mazumdar Rd, Delhi 110054, India. (author)
Chaudhary, VishakhaUniv Delhi, Dept Chem, North Campus, Delhi 110007, India.;Def Res & Dev Org, Div Cyclotron & Radiopharmaceut Sci, Inst Nucl Med & Allied Sci, Brig SK Mazumdar Rd, Delhi 110054, India. (author)
Pant, PradeepIndian Inst Technol, Dept Chem, New Delhi 110016, India. (author)
Jha, PreetiUppsala universitet,Medicinsk strålningsvetenskap(Swepub:uu)prejh226 (author)
Kumaran, Senthil S.All India Inst Med Sci, New Delhi 110029, India. (author)
Hussain, FirasatUniv Delhi, Dept Chem, North Campus, Delhi 110007, India. (author)
Mishra, Anil KumarDef Res & Dev Org, Div Cyclotron & Radiopharmaceut Sci, Inst Nucl Med & Allied Sci, Brig SK Mazumdar Rd, Delhi 110054, India. (author)
Univ Delhi, Dept Chem, North Campus, Delhi 110007, India.; Def Res & Dev Org, Div Cyclotron & Radiopharmaceut Sci, Inst Nucl Med & Allied Sci, Brig SK Mazumdar Rd, Delhi 110054, India.Def Res & Dev Org, Div Cyclotron & Radiopharmaceut Sci, Inst Nucl Med & Allied Sci, Brig SK Mazumdar Rd, Delhi 110054, India. (creator_code:org_t)

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In:Bioorganic chemistry: Elsevier1060045-2068

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