Development of a new 131I-labelled bisphosphonic acid for palliative therapy of metastatic bone pain

Full text: Approximately, 80% of all patients with cancer in advance stage could develop bone metastases. Nowadays, the management of metastatic bone pain remains controversial. Analgesics are widely described according to the World Health Organization analgesic ladder supplemented by local field, external beam irradiation for persisting skeletal symptoms. In the context of advancing malignancy, however, many patients progress to multi-site, poorly localized or migratory pain, which is less amenable to local field irradiation. Wide field, hemibody radiotherapy is useful in this setting, but it is limited by significant morbility, particularly gastrointestinal disturbance, when the abdomen and pelvis are included in the treatment field. The use of bone seeking radiopharmaceuticals represents a major advance in the management of refractory metastatic bone pain. Acting systemically, this approach allows multiple sites to be treated simultaneously with relatively sparing of healthy surrounding tissues. As a result, toxicity is low in comparison with other systemic therapies and treatment is well tolerated. Used isotopes for pain palliation by bone metastases are very expensive, with exception of 32P, which could cause bone-marrow depression. The aim of the present work was to develop a new bisphosphonic acid labeled with 131I for metastatic bone-pain palliation. An aryl-substituted bisphosphonic acid (PICIC-1), which would easily accept the 131I, was synthesized starting from DL-tyrosine. Reaction was made into three phases: 1. protection of amine group with methylchloroformiate; 2. phosphonation of carboxyl group by reaction with a mixture of phosphorous acid and phosphorous pentachloride and 3. deprotection of amine group by hydrolysis. The reaction yield was 60%. Purity of obtained compound was tested by reverse-phase HPLC using a RP18 column (4.6 mm x 100 mm) and a gradient from 0% to 100% of methanol in water as mobile phase. The chemical purity was higher 97%. The structure of the synthesized compound was analyzed by IR and NMR spectroscopy and by electrospray mass-spectrometry. The IR spectrum showed a wide peak due to the absorbed water, because the compound was highly hygroscopic. Despite, this peak hindered the interpretation of the spectrum, there were observed characteristic peaks of phosphonic groups and aromatic ring. NMR spectrum showed characteristic peaks corresponding to main functional groups of the molecule. Mass-spectrum showed two main peaks: one at 308.9 Da related with the loss of one OH group and the other at 325.1 Da corresponding to the molecular weight of attained bisphosphonic acid. Compound was labeled with 131I by using Chloramine-T method. Then, it was purified through AgCl filters. Labeling yield was higher 95%. The stability of the label was assessed up to 72 h in PBS 0.05 M pH = 7.0-7.2 and HSA. Just after 72 h incubation, the dehalogenation was significantly higher in HSA (∼15%) than in PBS. Biodistribution was studied in male Sprague Dawly rats (190-210g). Two hundred μCi (7.4 MBq) of 131I-PICIC-1 (0.1 mg) were injected through a lateral tail vein and organs were removed at 2 h, 24 h, 48 h. Scintigraphic images of the rats were performed up to 48h after intravenous administration of the radiopharmaceutical. Synthesized compound showed a bone uptake of 1.2% of administered dose per gram of tissue. Significative uptake was observed in kidneys and bowels, suggesting an excretion pathway by these organs. Skeleton of the rat was visualized in scintigraphic images, with an uptake proportional to metabolic activity. 1311I-labeled-PICIC-1 showed satisfactory bone affinity and could be a promising new radiopharmaceutical for metastatic bone-pain palliation. (author)