The synthesis and characterisation of new macrocyclic complexing agent for use in tumour targeting

Abstract

Macrocyclic complexing agents have been synthesised for the binding of indiumdil(III), gallium(III), yttrium(III), gold(I), silver(I) and rhenium(V) and a comparative study has been made between the macrocyclic complexing agents, 18N(_4)S(_2), 18N(_4)S(_2)Me(_4), 18N(_4)O(_2) and 18N(_4)0(_2)Me(_4) and their ability to bind silver (I). The gallium(III) and indium(III) complexes of 9N(_3)C(_3)Me(_3) and 9N(_3)C(_3)Ph(_3) have been investigated extensively both in vitro and in vivo. The stability of the complexes have been characterised using 71Ga NMR, 1H NMR, U.V. spectral analysis, ligand protonation constants, and complex binding constants. A full X-ray crystallographic structural determination has been obtained for the indium-9N(_3)C(_3)Me(_3) complex. Following confirmation of the excellent binding characteristics of the 9N(_3)C(_3)Me(_3) and 9N(_3)C(_3)Ph(_3) complexing agents, the in vivo kinetic stability of the indium and gallium complexes has been investigated. The 9N(_3)C(_3)Me(_3) complexes were exceptionally stable and cleared rapidly (99% within 24 hrs) via the renal excretion pathway. The complexes of the 9N(_3)C(_3)Ph(_3) were less stable and also showed a preference for clearance via the kidneys. Further to this, the tumour localising properties in a human melanotic melanoma has been investigated for the 67Ga- 9N(_3)C(_3)Ph(_3) complex. The complex has shown a preference for. tumour localisation, although a low tumour: blood ratio (1:1) may prohibit its application for tumour targeting. The stability constants of the silver(I) complexes of 18N(_4)S(_2), 18N(_4)S(_2)Me(_4), 18N(_4)O(_2) and 18N(_4)0(_2)Me(_4) have been measured both in methanolic and aqueous media. The [Ag-18N(_4)S(_2)Me(_4)]+ complex stability (log KmL= 14.6) is the highest stability constant recorded in methanol. In aqueous media, of the four complexes, the [Ag-18N(_4)S(_2)]+ is the most stable (log KmL=10-4) a reversal of the observed order of complex stability in methanol. The stability of the new yttrium(III) complexing agent has been ascertained using 1H NMR and HPLC radiometry and proved to be insufficiently stable for in vivo use, and was easily displaced by DTPA in a trial experiment.