Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1993-02-18
1995-05-09
Richter, Johann
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
562426, 562561, 562564, 562565, 5483181, 5483191, 5483195, C07C22904, C07C32114, C07D23304
Patent
active
054141141
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns a novel method for making compounds to be used in the field of administrable molecular carriers targeted for delivering paramagnetic MRI contrast enhancers to selected organs or tissues.
BACKGROUND OF THE INVENTION
Molecular conjugates in which a monoclonal or polyclonal antibody (cytoselective homing factor) is covalently linked to a moiety carrying aminopolycarboxylic chelatantS holding paramagnetic metal ions are known.
For instance, in W. T. ANDERSON et al., Cancer Res. 45 (1985), 2154-2158, there is disclosed the binding of up to 8 mol of DTPA per mol of antibody while retaining antibody activity and specificity. The DTPA (diethylenetriamine-pentaacetic acid) is a powerful chelatant for paramagnetic metal species including for instance Gd, Fe, Cr and Ni, which can therefore be directly targeted to specific cellular sites and aid MRI visualization by modifying proton spin relaxation (T.sub.1 and/or T.sub.2) and enhancing image contrast.
Also in WO-A-90/14881, there is disclosed the attachment of polyaminocarboxylic chelators to homing proteins by using bridging functional groups such as isocyanato-, isothiocyanato-, bromoacetamido-, diazo-, N-hydroxysuccinimide esters and inter-molecular or intra-molecular anhydrides.
However, the molecular ratio of chelatant to antibody was still too low for effective MRI contrast enhancement and means were developed which improved contrast enhancement efficiency. For instance, George W. and Catherine H. WU (WO-A-90/01900) have disclosed a conjugate in which a ligand such as a glycoprotein possessing exposed terminal galactose residues to be recognized by unique receptors at the surface of given types of cells is coupled to a chelating agent, e.g. DTPA or DOTA (1,4,7,10-tetrazacyclododecane-N.sub.4 -tetraacetic acid), capable of binding a paramagnetic species and form a stable and non-toxic complex. A selective protein was asialoorosomucoid (AsOR), and DTPA was coupled thereto by undisclosed means in order to eventually achieve a molar ratio of chelated Gd to AsOR in the range of 5:1 to 15:1 In another embodiment, polylysine (PL) was modified by reacting with the lactose terminals of the desialylated glycoprotein and thereafter with DTPA to yield an asia-PL-chelator conjugate. This conjugate was shown to achieve a binding of up to 90 mol of Gd per mol of lysine. Experimental details are however lacking in this reference. Y. MANABE et al., Biochim. & Biophys. Acta 883 (1986), 460-467, have disclosed making DTPA-linked poly(L-lysine) by reacting poly(L-lysine) of DP about 100 or so with DTPA cyclic anhydride (caDTPA), introduction therein of 2-pyridyldisulfide groups by reaction with N-succinimidyl-3-(2-pyridyldithio)-propionate (SPDP) and coupling with thiolated IgG to form a covalent thia-bonded conjugate. The reactions involved in this synthesis are summarized below. ##STR1##
A similar technique is disclosed by P. Shreve et al. in Magnetic Resonance in Medicine 3 (1986), 336-340.
P. F. Sieving et al., Bioconjugate Chem. 1 (1990), 65-71, have disclosed the binding of polyaminocarboxylic chelatants to the side-chain terminal --NH.sub.2 's of polylysine by means of a technique involving mixed anhydrides. The latter resulted from treating the chelates (e.g. DTPA and DOTA) in the form of their salts with organic amines such as triethylamine or tetramethylguanidine with isobutyl chloroformate (IBCF). The chelatant bearing polylysine was thereafter coupled to human serum albumin (HSA) as follows: Residual unreacted amine side groups of the polylysine were derivatized with succinimidyl-4-(N-maleinimidomethyl)-cyclohexane-1-carboxylate (SMCC) to provide maleinimido activated residues, while some free amino groups of the HSA were activated with 2-iminothiolane to provide at least one reactive alkylthiol group. Final coupling resulted from the addition of said thiol of the HSA to the double bond of the maleinimido terminals of the chelatant carrying polylysine. It was estimated that the conjugate obtained contained an average of about 70 chelat
REFERENCES:
patent: 4385169 (1983-05-01), Kato et al.
patent: 5087616 (1992-02-01), Myers et al.
Chemical Abstracts, 94(21):172633 (1981).
Medline Abstracts, AN:91248849 (1981).
Chemical Abstracts, 112(7):51816 (1986).
Bracco International B.V.
Hydorn Michael B.
Richter Johann
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