Derivatives of 1,3,5-Triamino-1,3,5-trideoxy-cis-inositol as Versatile Pentadentate Ligands for Protein Labeling with Re-186/188. Prelabeling, Biodistribution, and X-ray Structural Studies
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- 作者：Andreas Kramer ; Roger Alberto ; André ; Egli ; Ilse Novak-Hofer ; Kaspar Hegetschweiler ; Ulrich Abram ; Paul V. Bernhardt ; and P. August Schubiger
- 刊名：Bioconjugate Chemistry
- 出版年：1998
- 出版时间：November 1998
- 年：1998
- 卷：9
- 期：6
- 页码：691 - 702
- 全文大小：369K
- 年卷期：v.9,no.6(November 1998)
- ISSN：1520-4812
文摘
The pentadentate H3bhci [1,3,5-trideoxy-1,3-bis((2-hydroxybenzyl)amino)-cis-inositol] and its bifunctionalized analogue H3bhci-glu-H [1,3,5-trideoxy-1,3-bis((2-hydroxybenzyl)amino)-5-glutaramido-cis-inositol] were synthesized, and their coordination chemistry was investigated with inactive rhenium,with no carrier added Re-188 and with carrier added Re-186. The neutral Re(V) complexes [ReO(bhci)] and [ReO(bhci-glu-H)] are formed in good yields starting from [ReOCl3(P(C6H5)3)2] or inquantitative yield directly from [186/188ReO4]- in aqueous solution by reduction with Sn(II) or Sn(0).The X-ray structures of [ReO(bhci)] and [ReO(bhci-glu-H)] were elucidated revealing pentadentate"side on" coordination of the ligands to the "Re=O" core. The basic cyclohexane frame adopts a chairform in the case of [ReO(bhci)] and a twisted boat form in the case of [ReO(bhci-glu-H)]. [ReO(bhci)]crystallizes in the monoclinic space group C2/c with a = 27.425(3), b = 14.185(1), c = 19.047(2) Å, and
= 103.64(2)
and [ReO(bhci-glu-H)] in the monoclinic space group P21/c with a = 13.056(3), b =10.180(1), c = 22.378(5) Å, and = 98.205(9). Both 188Re complexes are stable in human serum forat least 3 days without decomposition. After injection into mice, [ReO(bhci-glu)]- is readily excretedthrough the intestines, while [ReO(bhci)] is excreted by intestines, liver, and the kidneys. TLCinvestigations of the urine showed exclusively the complexes [ReO(bhci-glu-H)] and [ReO(bhci)],respectively, and no decomposition products. For derivatization of antibodies, the carboxylic groupof [ReO(bhci-glu-H)] was activated with N-hydroxysuccinimide, which required unusually vigorousreaction conditions (heating). The anti colon cancer antibody mAb-35 [IgG and F(ab')2 fragment] waslabeled with [186/188ReO(bhci-glu)] to a specific activity of up to 1.5 mCi/mg (55 MBq/mg) with fullretention of immunoreactivity. Labeling yields followed pseudo-first-order kinetics in antibodyconcentration with the ratio of rates between aminolysis and hydrolysis being about 2. Biodistributionsof 186Re-labeled intact mAb-35 as well as of its F(ab')2 fragment in tumor-bearing nude mice revealedgood uptake by the tumor with only low accumulation of radioactivity in normal tissue.
= 103.64(2) and [ReO(bhci-glu-H)] in the monoclinic space group P21/c with a = 13.056(3), b =10.180(1), c = 22.378(5) Å, and = 98.205(9). Both 188Re complexes are stable in human serum forat least 3 days without decomposition. After injection into mice, [ReO(bhci-glu)]- is readily excretedthrough the intestines, while [ReO(bhci)] is excreted by intestines, liver, and the kidneys. TLCinvestigations of the urine showed exclusively the complexes [ReO(bhci-glu-H)] and [ReO(bhci)],respectively, and no decomposition products. For derivatization of antibodies, the carboxylic groupof [ReO(bhci-glu-H)] was activated with N-hydroxysuccinimide, which required unusually vigorousreaction conditions (heating). The anti colon cancer antibody mAb-35 [IgG and F(ab')2 fragment] waslabeled with [186/188ReO(bhci-glu)] to a specific activity of up to 1.5 mCi/mg (55 MBq/mg) with fullretention of immunoreactivity. Labeling yields followed pseudo-first-order kinetics in antibodyconcentration with the ratio of rates between aminolysis and hydrolysis being about 2. Biodistributionsof 186Re-labeled intact mAb-35 as well as of its F(ab')2 fragment in tumor-bearing nude mice revealedgood uptake by the tumor with only low accumulation of radioactivity in normal tissue.