Synthesis of trans-1,2-cyclohexyldinitrilo tetramethylene phosphonic acid and its radiolabelling with 99mTc for the detection of skeletal metastases.

BACKGROUND AND AIM

The development of bone-seeking radiopharmaceuticals for the detection of malignant bone lesions could further improve the diagnostic accuracy of routine bone scanning. This study aimed to provide a convenient synthesis of trans-1,2-cyclohexylenedinitrilo tetramethylene phosphonic acid (CDTMP) and an improved preparation of its (99m)Tc complex.

METHODS

CDTMP was prepared from trans-1,2-cyclohexyldinitrilotetraacetic acid by reaction with phosphorus trichloride and it was labelled with (99m)Tc. Toxicity and biodistribution studies were carried out in BALB/c mice, while blood clearance and bone scintigraphy studies were carried out in rabbits. (99m)Tc-CDTMP was evaluated for the detection of malignant bone lesions in 11 patients. Bone scintigraphy (a methylene diphosphonate scan) was performed to detect metastases at diagnosis and follow-up.

RESULTS

The radiolabelling efficiency was found to be >97% and the stability in serum indicated that (99m)Tc remained bound to the chelate, CDTMP, for up to 24 h. Blood clearance showed a quick wash-out from the circulation and the biological half-lives (t12) were 55 min (F) and 8 h 48 min (S). The LD50 was 110 mg.kg(-1) as determined by toxicity studies. The drug was excreted mainly through renal route and the accumulation of (99m)Tc-CDTMP in bone was 7.69+/-0.65%ID/g at 1 h. The mean ratio of bone lesion to soft tissue was 6.8+/-0.69 and of bone lesion to normal bone was 5.67+/-0.82. Visual image analysis of (99m)Tc-CDTMP was clinically comparable to the interpretation of imaging studies with (99m)Tc-MDP.

CONCLUSION

These preliminary data support increased bone uptake by the tetraphosphonate complex of (99m)Tc. This suggests that CDTMP complexed with therapeutic radionuclides should be evaluated for therapy of skeletal metastases.