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

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Abstract

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 99mTc complex.

Methods

CDTMP was prepared from trans-1,2-cyclohexyldinitrilotetraacetic acid by reaction with phosphorus trichloride and it was labelled with 99mTc. Toxicity and biodistribution studies were carried out in BALB/c mice, while blood clearance and bone scintigraphy studies were carried out in rabbits. 99mTc-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 99mTc 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 99mTc-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 99mTc-CDTMP was clinically comparable to the interpretation of imaging studies with 99mTc-MDP.

Conclusion

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

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