Synthesis of novel bifunctional chelators and their use in preparing monoclonal antibody conjugates for tumor targeting

Journal Article · Sat Dec 31 23:00:00 EST 1988 · J. Med. Chem.; (United States)

DOI:https://doi.org/10.1021/jm00121a042· OSTI ID:6568539

Westerberg, D A; Carney, P L; Rogers, P E; Kline, S J; Johnson, D K

Bifunctional derivatives of the chelating agents ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid, in which a p-isothiocyanatobenzyl moiety is attached at the methylene carbon atom of one carboxymethyl arm, was synthesized by reductive alkylation of the relevant polyamine with (p-nitrophenyl)pyruvic acid followed by carboxymethylation, reduction of the nitro group, and reaction with thiophosgene. The resulting isothiocyanate derivatives reacted with monoclonal antibody B72.3 to give antibody-chelator conjugates containing 3 mol of chelator per mole of immunoglobulin, without significant loss of immunological activity. Such conjugates, labeled with the radioisotopic metal indium-111, selectively bound a human colorectal carcinoma implanted in nude mice when given intravenously. Uptake into normal tissues was comparable to or lower than that reported for analogous conjugates with known bifunctional chelators. It is concluded that substitution with a protein reactive group at this position in polyaminopolycarboxylate chelators does not alter the chelating properties of these molecules to a sufficient extent to adversely affect biodistribution and thus provides a general method for the synthesis of such chelators.

• Research Organization: Abbott Laboratories, Abbott Park, IL (USA)
• OSTI ID: 6568539
• Journal Information: J. Med. Chem.; (United States), Journal Name: J. Med. Chem.; (United States) Vol. 32:1; ISSN JMCMA
• Country of Publication: United States
• Language: English

Related Subjects

550601* -- Medicine-- Unsealed Radionuclides in Diagnostics
62 RADIOLOGY AND NUCLEAR MEDICINE
ALKYLATION
AMINO ACIDS
ANIMALS
ANTIBODIES
BETA DECAY RADIOISOTOPES
BODY
CARBOXYLIC ACIDS
CARCINOMAS
CHELATING AGENTS
CHEMICAL PREPARATION
CHEMICAL REACTIONS
DAYS LIVING RADIOISOTOPES
DIAGNOSIS
DIGESTIVE SYSTEM
DISEASES
DISTRIBUTION
DRUGS
DTPA
EDTA
ELECTRON CAPTURE RADIOISOTOPES
EXPERIMENTAL NEOPLASMS
GASTROINTESTINAL TRACT
GLOBULINS
IMMUNOGLOBULINS
INDIUM 111
INDIUM ISOTOPES
INTERMEDIATE MASS NUCLEI
INTESTINES
ISOMERIC TRANSITION ISOTOPES
ISOTOPES
LABELLED COMPOUNDS
LARGE INTESTINE
MAMMALS
MICE
MINUTES LIVING RADIOISOTOPES
MONOCLONAL ANTIBODIES
NEOPLASMS
NUCLEI
ODD-EVEN NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PROTEINS
RADIOISOTOPES
RADIOPHARMACEUTICALS
RADIOPROTECTIVE SUBSTANCES
RECTUM
RODENTS
STRUCTURE-ACTIVITY RELATIONSHIPS
SYNTHESIS
TISSUE DISTRIBUTION
UPTAKE
VERTEBRATES