Development of novel bifunctional chelating agents containing rigid cyclic hydrocarbon backbones
- Brookhaven National Laboratory, Upton, NY (United States); and others
We are developing a new class of ligands in which the metal-binding polyaminocarboxylate groups are incorporated onto rigid cyclic hydrocarbon backbones. These ligands, with increased preorganization, should produce radiometal-bioconjugates with higher in-vivo stability. The synthesis of the first in this series of ligands (2,3-diaminobicyclo[2.2.2] octanetetraacetic acid, BODTA) began with a Diels-Alder reaction of 1,3-diacetylimidazolin-2-one and 1,3-cyclohexadiene. Base hydrolysis, alkylation with ethyl iodoacetate, hydrolysis of the esters, and catalytic hydrogenation gave BODTA. For conjugation to MAbs, an average of one COOH group of unsaturated BODTA was converted into an NHS ester using 0.8 equivalent of DCC. The second ligand under development is the decadentate tethered bis-cyclohexyl-EDTA (bis-CDTA) in which 2 cyclohexyl rings are tied together with an ethylene tether. Acylation of monotrityl-1,2-diaminocyclohexane with the di-NHS ester of oxalic acid, reduction of the amide moieties, and removal of the trityl groups followed by cyanomethylation has afforded a hexanitrile whose hydrolysis will produce tethered bis-CDTA. An anti-CEA F(ab{prime}){sub 2} MAb was conjugated with an average of 0.6 BODTA per MAb molecule, labeled with Co-57, and purified by size-exclusion HPLC. Stability of this radioconjugate in mouse serum at 48 h was somewhat better (2% loss) than that of the conventional DTPA-dianhydride (DTPA-DA) conjugate (8% loss). In human tumor-xenografted nude mice (LS-174T cells), tumor (T), blood (B), liver (L), and kidney (K) uptakes (% ID/g) at 24h were: TODTA, 21.6, 4.4, 4.8, 6.0; DTPA-DA, 13.6, 2.5, 5.0, 2.9. The tumor to normal tissue ratios at 48 h for BODTA and DTPA-DA respectively were: T/B, 18.0, 13.9; T/L 4.9, 2.3; T/K, 5.4, 3.9. These preliminary results show promise for using the basic BODTA structure to produce improved bioconjugates with small radiometal ions.
- Research Organization:
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- DOE Contract Number:
- AC02-76CH00016
- OSTI ID:
- 441598
- Report Number(s):
- CONF-950603-; ISSN 0161-5505; TRN: 96:002093-0023
- Journal Information:
- Journal of Nuclear Medicine, Vol. 36, Issue Suppl.5; Conference: 42. annual meeting of the Society of Nuclear Medicine, Minneapolis, MN (United States), 12-15 Jun 1995; Other Information: PBD: May 1995
- Country of Publication:
- United States
- Language:
- English
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