当前位置： SCI文献检索 > MOLECULAR PHARMACEUTICS期刊下所有文献 > Multifunctional Desferrichrome Analogues as Versatile 89Zr(IV) Chelators for ImmunoPET Probe Development.

Multifunctional Desferrichrome Analogues as Versatile 89Zr(IV) Chelators for ImmunoPET Probe Development.

Abstract：

:New bifunctional hexa- and octadentate analogues of the hydroxamate-containing siderophore desferrichrome (DFC) have been synthesized and evaluated as 89Zr-chelating agents for immunoPET applications. The in vitro and in vivo inertness of these new ligands, Orn3-hx (hexadentate) and Orn-4hx derivatives (octadentate), was compared to the gold standard hexadentate, hydroxamate-containing chelator for 89Zr desferrioxamine (DFO). Density functional theory was employed to model the geometries of the resulting Zr(IV) complexes and to predict their relative stabilities as follows: Zr(Orn4-hx) > Zr(DFC) > Zr(Orn3-hx). Transchelation challenge experiments of the corresponding radiochemical complexes with excess ethylenediaminetetraacetate (EDTA) indicated complex stability in accordance with DFT calculations. Radiolabeling of these ligands with 89Zr was quantitative (0.25 μmol of ligand, pH 7.4, room temperature, 20 min). For antibody conjugation, the isothiocyanate (NCS) functional group was introduced to the N terminus of Orn3-hx and Orn-4hx. An additional trifunctional derivative that bears a silicon-rhodamine fluorophore on the C-terminus and NCS on the N terminus was also furnished. As proof of concept, all NCS derivatives were conjugated to the HER2-targeting antibody, trastuzumab. Radiolabeling of immunoconjugates with 89Zr was accomplished with radiochemical yields of 16 ± 2% to 95 ± 2%. These constructs were administered to naive mice (male, C57BL/6J, n = 4) to assess in vivo inertness, which is inversely correlated with uptake of 89Zr in bone, after 96 h circulation time. We found bone uptake to range from 7.0 ± 2.2 to 10.7 ± 1.3% ID/g, values that compare well to the corresponding DFO conjugate (7.1 ± 0.8% ID/g). In conclusion, we have rationally designed linear, bifunctional and trifunctional desferrichrome analogues suitable for the mild and inert radiolabeling of antibodies with the radionuclide 89Zr.

journal_name

Mol Pharm

journal_title

Molecular pharmaceutics

authors

Adams CJ,Wilson JJ,Boros E

doi

10.1021/acs.molpharmaceut.7b00343

subject

Has Abstract

pub_date

2017-08-07 00:00:00

pages

2831-2842

issue

eissn

1543-8384

issn

1543-8392

journal_volume

pub_type

杂志文章

在线工具

Multifunctional Desferrichrome Analogues as Versatile 89Zr(IV) Chelators for ImmunoPET Probe Development.