Preparation and biological evaluation of cyclopentadienyl-based 99mTc-complexes [(Cp-R)99mTc(CO)3] mimicking benzamides for malignant melanoma targeting☆

Abstract

The biological evaluation of half-sandwich 99mTc-complexes that surrogate iodobenzamide with a high affinity for melanin tumor tissue is described. We have synthesized via retro Diels–Alder reaction two models of 99mTc complexes which possess the piano stool [Cp99mTc(CO)3] motif instead of a phenyl ring as in the original iodobenzamide 123I-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide (2-IBP) and N-(2-diethylaminoethyl)-4-iodobenzamide (BZA). Diels–Alder products 2a–b (HCp-CONHR)2 (2a, R=2-diethylaminoethyl; 2b, R=benzylpiperidin-4-yl) were prepared and reacted with fac-[99mTc(H2O)3(CO)3)]+ 1 in water to produce the corresponding 99mTc complexes [(2a)99mTc(CO)3)] 4a and [(2b)99mTc(CO)3)] 4b. The structures of the 99mTc complexes on the no-carrier-added level have been confirmed by chromatographic comparison with the corresponding rhenium complexes 3a and 3b, macroscopically characterized by IR, NMR, ESI-MS and X-ray crystallography for 3a [triclinic, P-1, a=7.3518(1) Å, b=8.0309(2) Å, c=17.5536(3) Å, α=99.1260(5)°, β=90.4215(14)°, γ=117.0187(11)°]. The radioconjugate 4b showed good in vitro stability. In murine melanoma B16F1 cells, significant cellular uptake (43.9% of the total applied activity) was attained after 4 h at 37°C with about 50% of the cell-associated radioactivity being internalized in the cells (22% of the applied activity). Furthermore, in melanoma-bearing C57BL6 mice, tumor uptake values of 3.39±0.50 %ID g−1 and 3.21±0.26 %ID g−1 at 1 and 4 h postinjection, respectively, were observed indicating a good retention of 4b in the tumor.