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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.


Kramer, A; Alberto, R; Egli, A; Novak-Hofer, I; Hegetschweiler, K; Abram, U; Bernhardt, P V; Schubiger, P A (1998). 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. Bioconjugate Chemistry, 9(6):691-702.

Abstract

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 in quantitative 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 chair form 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) A, and beta = 103.64(2) degrees 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) A, and beta = 98.205(9) degrees. Both 188Re complexes are stable in human serum for at least 3 days without decomposition. After injection into mice, [ReO(bhci-glu)]- is readily excreted through the intestines, while [ReO(bhci)] is excreted by intestines, liver, and the kidneys. TLC investigations 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 group of [ReO(bhci-glu-H)] was activated with N-hydroxysuccinimide, which required unusually vigorous reaction conditions (heating). The anti colon cancer antibody mAb-35 [IgG and F(ab')2 fragment] was labeled with [186/188ReO(bhci-glu)] to a specific activity of up to 1.5 mCi/mg (55 MBq/mg) with full retention of immunoreactivity. Labeling yields followed pseudo-first-order kinetics in antibody concentration with the ratio of rates between aminolysis and hydrolysis being about 2. Biodistributions of 186Re-labeled intact mAb-35 as well as of its F(ab')2 fragment in tumor-bearing nude mice revealed good uptake by the tumor with only low accumulation of radioactivity in normal tissue.

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 in quantitative 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 chair form 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) A, and beta = 103.64(2) degrees 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) A, and beta = 98.205(9) degrees. Both 188Re complexes are stable in human serum for at least 3 days without decomposition. After injection into mice, [ReO(bhci-glu)]- is readily excreted through the intestines, while [ReO(bhci)] is excreted by intestines, liver, and the kidneys. TLC investigations 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 group of [ReO(bhci-glu-H)] was activated with N-hydroxysuccinimide, which required unusually vigorous reaction conditions (heating). The anti colon cancer antibody mAb-35 [IgG and F(ab')2 fragment] was labeled with [186/188ReO(bhci-glu)] to a specific activity of up to 1.5 mCi/mg (55 MBq/mg) with full retention of immunoreactivity. Labeling yields followed pseudo-first-order kinetics in antibody concentration with the ratio of rates between aminolysis and hydrolysis being about 2. Biodistributions of 186Re-labeled intact mAb-35 as well as of its F(ab')2 fragment in tumor-bearing nude mice revealed good uptake by the tumor with only low accumulation of radioactivity in normal tissue.

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Additional indexing

Item Type:Journal Article, refereed
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:November 1998
Deposited On:11 Feb 2008 12:25
Last Modified:05 Apr 2016 12:20
Publisher:American Chemical Society
ISSN:1043-1802
Publisher DOI:10.1021/bc980014i
PubMed ID:9815162

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