131I labeled diphosphonates for the palliative treatment of bone metastases--IV. Syntheses of benzylidenediphosphonates and their organ distribution in rats.

Palliative treatment of bone pain induced by disseminated bone metastases can be performed with osteotropic, beta(-)-emitting radionuclides. Newly developed 131I labeled benzylidenediphosphonic acid (BDP) derivatives show osteotropic characteristics which suggest that they might possibly be useful radiopharmaceuticals for that purpose. Six BDP derivatives were synthesized with H, OH or NH2 in the 4- and alpha-position. Syntheses were performed by the formal addition of 2 mol of phosphorous acid in the presence of PBr3 to 1 mol of the respective benzonitrile. Transformation of the 4-methoxy and 4-nitro substituents, which were stable during the diphosphonate formation, to 4-HO and 4-NH2 was achieved by hydrolytic ether cleavage in boiling HBr and catalytic hydrogenation with Pd/C, respectively. Transformation of the alpha-amino to alpha-hydroxy group was achieved by the action of NaNO2 in HCl. 4-Hydroxybenzylidenediphosphonic acid (9) was formed unexpectedly during the reaction of 4-hydroxybenzoic acid with H3PO3/PBr3. The addition of 2 mol of phosphorous acid to the benzoic acid was accompanied by an additional reduction at the alpha-carbon. The new BDP derivatives were analyzed by HPLC, NMR and elemental analysis. After labeling with 131I the BDP derivatives were tested in female Sprague-Dawley rats to obtain organ uptake and kinetic data. The various substituents showed an influence on the bone affinity and the uptake in other organs. Among the BDP derivatives tested alpha-amino-(3-[131I]iodo-4-hydroxybenzylidene)diphosphonate (4a) showed the best biological characteristics.