Cyclopentadienyl-Based Amino Acids (Cp-aa) As Phenylalanine Analogues for Tumor Targeting: Syntheses and Biological Properties of [(Cp-aa)M(CO)3](M = Mn, Re, 99mTc)

Due to an enhanced demand for amino acids, the L-type amino acid transporter 1 (LAT1) is overexpressed in many tumor cell lines. LAT1 represents therefore an attractive target for cancer therapy and diagnosis. On the basis of our reported aqueous synthesis of [(Cp-R)Tc-99m(CO)(3)]-type complexes,(1-S) we describe the preparation of unnatural amino acid analogues [(Cp-CH2CH(NH2)COOH)Mn(CO)(3)] and [(Cp-CH(NH2)COOH)M(CO)(3)] (M = Mn, Re, Tc-99m). Starting from fully protected HC5H5-aa (aa = amino acid), [(Cp-aa)Tc-99m(CO)(3)] complexes are accessible in quantitative yields and in a one-step synthesis from [(TcO4)-Tc-99m](-). The rhenium and manganese analogues were prepared and structurally characterized to confirm the authenticity of the Tc-99m complex. The inhibition constant of natural phenylalanine (phe) for LAT1 is in the range 70 +/- 10 mu M. The K-i value of [(Cp-CH(NH2)COOH)Mn(CO)(3)] (1a) is 53 +/- 11 mu M, whereas K-i for the "true" phe analogue [(Cp-CH2CH(NH2)COOH)Mn(CO)(3)] (2) was surprisingly high at 277 +/- 37 mu M. Complex la caused efflux when exposed to cells, underlining its active transport by LAT1 into the cell. Tc-99m analogues of small biological lead structures such as amino acids are generally not recognized anymore by their targets, in particular by trans-membrane transporters. The bioorganometallic analogues presented here are, however, actively transported and corroborate the importance of organometallic complexes as mimics of organic lead structures in life sciences.