Novel tumourtropic ester derivatives of ^99mTc(V)-mesoDMSA with low affinity for bone tissue

Starting from our previous finding that pentavalent ^99m Tc(V)DMSA, a useful agent for localization of osteosarcoma and bone metastases, already loses its bone affinity when one ester group is introduced into the complex molecule we studied the impact of esterification in more detail. This paper reports on the evaluation of various ^99mTc(V)DMS ester complexes in rats and tumour-bearing nude mice with regard to their tumour retention and improvement of the tumour to tissue ratios. The distribution patterns of the complexes A ([ ^99m TcO(DMSA) ₂]^-), B ([^99mTcO(DMSA/DMSEt)]^-) and C ([^99mTcO(DMSEt)₂]^-) are gradually changed with the number of ester groups in the anionic complex. However, the asymmetric diester complex D ([^99mTcO(DMSA/DMSEt₂)]^-) is very slowly cleared, especially from the blood of nude mice. Moreover, this complex differs significantly from the symmetric complex C in its elimination behaviour from the liver and kidneys. The tumour uptake is maintained with complexes which contain one or two non-hydrolyzable ester functions. Preliminary biodistribution studies of the monoethyl and diethyl ester complexes B, C, and D in comparison with A in tumour-bearing nude mice showed similar uptake into the human squamous cell carcinoma (FaDu) as well as into the human colonic cell carcinoma (HT29) of nude mice. The low bone accumulation of B, C and D results in excellent tumour to bone ratios, e.g. approx. 3:1 for the ester complex B compared to approx. 1:2 for complex A. Differences were observed in the accumulation and elimination behaviour of the complexes A and B in various bone structures of rats. The age-dependent uptake of A and B was compared in long bone (femur) and in cranial bone of rats. The results suggest that ester-functionalized ^99mTc(V)DMS complexes and their ¹⁸⁸Re analogues may be superior to ^99mTc(V)/¹⁸⁸Re(V)DMSA in diagnostic and therapeutic nuclear medicine.