Tumour targeting with macrocyde conjugates

Abstract

Complexes of the radionuclides (^67)Ga and (^III)In, or of the paramagnetic contrast agent Gd, used in MRI, provide a means of imaging tumours. The stability of the (^71)Ga- NOTA complex was verified by in vivo NMR spectroscopy. The novel phosphinic acid NOTA analogue, bearing an isopropyl substituent on phosphorus was prepared and its lipophilicity and (^III)In biodistribution in mice determined. The crystal structure of the yttrium complex of N,N"-bis(benzylcarbamoylmethyl)diethylenetriamine-N,N',N"-triacetic acid revealed amide carbonyl ligation in a distorted mono-capped square antiprismatic structure, with one metal-bound water. The biodistribution of the analogous Gd complex was examined. A novel series of 9N3 based ligands incorporating three further N donor atoms, carboxymethyl groups and a potentially larger cavity size were synthesised. The analogous series containing phosphinic acid groups and the 12N3 counterparts were also prepared. The former series formed complexes with Gd and the biodistribution in mice was studied. The 12N3 analogues failed to form Gd complexes.2-Nitroimidazoles are known to selectively target hypoxic tumour tissue. Two conjugates of 2-nitroimidazole for tumour imaging were prepared, the Gd complex of a DTPA-bis(2-nitroimidazole) amide and the (^III)In complex of a C-functionalised NOTA- nitroimidazole conjugate. The biodistribution in mice of each was studied and luminescence experiments on the Tb complex of the former revealed one metal bound water molecule. Novel conjugates of the tetrapeptide tuftsin and a complexing agent based on the 12N4 skeleton and an N-linked NOTA derivative were synthesised. Biodistributions of the Gd and In complexes respectively are being carried out. Acridine intercalators reversibly bind DNA, possibly enhancing the effectiveness of tumour targeting conjugates. Novel multifunctionally labelled acridines based on tris(2- aminoethyl) amine were sought. The p-nitrophenolate active ester of 9-acridine carbamoyl-2-(2-aminoethyl)-2-methyl amine was also prepared as a versatile agent for acridine labelling.