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 99m Tc-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 99m Tc complexes which possess the piano stool [Cp 99m Tc(CO) 3 ] motif instead of a phenyl ring as in the original iodobenzamide 123 I- 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- [ 99m Tc(H 2 O) 3 (CO) 3 )] + 1 in water to produce the corresponding 99m Tc complexes [(2a) 99m Tc(CO) 3 )] 4a and [(2b) 99m Tc(CO) 3 )] 4b. The structures of the 99m Tc 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) A, b =8.0309(2) A, c =17.5536(3) A, 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.