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5-HT 1A targeting PARCEST agent DO3AM-MPP with potential for receptor imaging: Synthesis, physico-chemical and MR studies.
5-HT 1A targeting PARCEST agent DO3AM-MPP with potential for receptor imaging: Synthesis, physico-chemical and MR studies.
- Source :
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Bioorganic chemistry [Bioorg Chem] 2021 Jan; Vol. 106, pp. 104487. Date of Electronic Publication: 2020 Nov 24. - Publication Year :
- 2021
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Abstract
- Contrast enhancement in MRI using magnetization or saturation transfer techniques promises better sensitivity, and faster acquisition compared to T <subscript>1</subscript> or T <subscript>2</subscript> contrast. This work reports the synthesis and evaluation of 5-HT <subscript>1A</subscript> targeted PARACEST MRI contrast agent using 1,4,7,10-tetraazacycloDOdecane-4,7,10-triacetAMide (DO3AM) as the bifunctional chelator, and 5-HT <subscript>1A</subscript> -antagonist methoxyphenyl piperazine (MPP) as a targeting unit. The multi-step 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 <subscript>M</subscript> -H <subscript>2</subscript> O) of 2.7 Å and water residence time (τ <subscript>m</subscript> ) of 0.23 ms. The dissociation constant of K <subscript>d</subscript> 62 ± 0.02 pM as evaluated from fluorescence quenching of 5-HT <subscript>1A</subscript> (protein) and docking score of -4.81 in theoretical evaluation reflect the binding potential of the complex Gd-DO3AM-MPP with the receptor 5-HT <subscript>1A</subscript> . Insights of the docked pose reflect the importance of NH <subscript>2</subscript> (amide) and aromatic ring in Gd-DO3AM-MPP while interacting with Ser 374 and Phe 370 in the antagonist binding pocket of 5-HT <subscript>1A</subscript> . Gd-DO3AM-MPP shows longitudinal relaxivity 5.85 mM <superscript>-1</superscript> s <superscript>-1</superscript> with a water residence lifetime of 0.93 ms in hippocampal homogenate containing 5-HT <subscript>1A</subscript> . The potentiometric titration of DO3AM-MPP showed strong selectivity for Gd <superscript>3+</superscript> over physiological metal ions such as Zn <superscript>2+</superscript> and Cu <superscript>2+</superscript> . The in vitro and in vivo studies confirmed the minimal cytotoxicity and presential binding of Gd-DO3AM-MPP with 5-HT <subscript>1A</subscript> receptor in the hippocampus region of the mice. Summarizing, the complex Gd-DO3AM-MPP can have a potential for CEST imaging of 5-HT <subscript>1A</subscript> receptors.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Cell Survival drug effects
Contrast Media chemical synthesis
Contrast Media chemistry
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Molecular Structure
Propiophenones chemistry
Serotonin 5-HT1 Receptor Antagonists chemical synthesis
Serotonin 5-HT1 Receptor Antagonists chemistry
Structure-Activity Relationship
Contrast Media pharmacology
Magnetic Resonance Imaging
Propiophenones pharmacology
Receptor, Serotonin, 5-HT1A metabolism
Serotonin 5-HT1 Receptor Antagonists pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 106
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33339667
- Full Text :
- https://doi.org/10.1016/j.bioorg.2020.104487