Karl J. Jankowski

The in vivo release of 90Y from cyclic and acyclic ligand-antibody conjugates

Yttrium binding ligands DOTA, caDTPA and CT-DTPA were each conjugated to monoclonal antibody B72.3, labelled with 90Y and injected into mice in order to assess the in vivo inertness of the antibody-linked 90Y-ligand complexes. Levels of 90Y in femur shafts of the DOTA-B72.3 mice were low, being approximately 7 and 44%, respectively, of levels in the femur shafts of the caDTPA-B72.3 and CT-DTPA-B72.3 treated mice. This finding demonstrates the greater inertness and by implication the greater suitability for immunotherapy of the DOTA-90Y complex.

Synthesis of a kinetically stable yttrium-90 labelled macrocycle–antibody conjugate

Lysine is a precursor for the synthesis of an aminobutyl C-functionalised tetra-azacyclododecane tetra-acid which has been linked to B72.3 antibody and may be labelled with 90Y to form a kinetically stable complex of potential use in radioimmunotherapy.

Towards tumour imaging with indium-111 labelled macrocycle–antibody conjugates

C-Functionalised triazacyclododecane and triazacyclononane triacid macrocycles have been covalently attached to a monoclonal antibody and may be labelled with 111In to form kinetically inert radiolabelled complexes.

Implementation of macrocycle conjugated antibodies for tumour-targetting

Monoclonal antibodies may be selectively functionalised with macrocyclic ligands, permitting the transport of an imaging or c totoxic metal radionuclide specifically to a tumour. Antibodies conju ated to p13) and (14)-membered tetraazamacrocycles allow 64Cu or 67Cu labefled antibody to be used for imaging or therapy.

Synthesis of C- and N-functionalised derivatives of 1,4,7-triazacyclononane-1,4,7-triyltriacetic acid (NOTA), 1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetrayltetra-acetic acid (DOTA), and diethylenenetriaminepenta-acetic acid (DTPA): bifunctional complexing agents for the derivatisation of antibodies

Using (2S)-lysine as a precursor, the syntheses of aminobutyl derivatives of 1,4,7-triazacyclononane, 1,4,7,10-tetra-azacyclododecane, and 3-azapentane-1,5-diamine are described. Transformation into their reactive maleimide derivatives is described and alternative strategies for synthesising the title complexing agents involving nitrogen functionalisation are defined.

Synthesis and complexation behaviour of an effective octadentate complexone 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis[methylene(methylphosphinic acid)]

The title ligand and a C-functionalised analogue have been prepared; the ligand is very strongly basic [pKa LH+, LH2+ < 14 (298 K)] and forms remarkably stable complexes with yttrium and calcium.

Synthesis and complex stability of parent and C-functionalised derivatives of 1,4,7-triazacyclononane-1,4,7-tris[methylene(methylphosphinic acid)]: an effective new complexing agent

The title ligand forms kinetically stable complexes with indium and gallium and exhibits a marked selectivity (105.6) for binding Mg2+ over Ca2+ in aqueous solution.

Syntheses of C- and N-functionalised derivatives of 1,5,9-triazacyclododecane

The synthesis of a series of di- and tri-N-substituted triazacyclododecane ligands has been effected through the intermediary of monotosylamide derivatives. A C-functionalised aminobenzyl [12]-N3 tris(carboxymethyl) derivative has been prepared permitting subsequent linkage to a protein.

Studies related to penicillins. Part 28. β-Elimination reactions of sulphones derived from penicillins leading to cis-3-acylamino-4-oxoazetidine-2-sulphinic acids

The reactions of the 3-acetyl and 3-formyl derivatives of (3S,5R,6R)-2,2-dimethyl-6-phenoxyacetamidopenam 1,1-dioxide, i.e. compounds (5e,f), and of p-nitrophenyl (3S,5R,6R)benzylpenicillinate 1,1-dioxide (1f) with 1,5-diazabicyclo[5.3.0]non-5-ene (DBN) followed by iodomethane have been studied. In the case of penam dioxide (5e), epimerisation at position 6 competes with the β-elimination at position 3 and a mixture of the trans- and cis-azetidinones (11a) and (12a) is isolated. No epimerisation is observed with compounds (5f) and (1f), which react to give the corresponding cis-azetidinones (12b,c). It is possible to avoid the epimerisation of the penam dioxide (5e), and to isolate the cis-azetidinesulphinate salt (13), by using potassium t-butoxide in place of DBN. The cis-azetidinesulphinic acid (8c) is also isolable from the reaction of the penicillinate dioxide (1f) with DBN followed by acidic work-up. It undergoes O-methylation of the sulphinic acid group in the presence of diazomethane to give the methyl sulphinate (19), as a mixture of diastereoisomers. Saponification of the p-nitrophenyl ester of the cis-azetidinesulphinic acid (8c) is effected by sodium hydroxide to give the disodium salt (18b), which undergoes methylation in the presence of iodomethane to afford the dimethyl derivative (12d).