S ‐Functionalized Cysteine: Powerful Ligands for the Labelling of Bioactive Molecules with Triaquatricarbonyltechnetium‐99m(1+) ([ 99m Tc(OH 2 ) 3 (CO) 3 ] + )

S ‐Alkylated cysteines are used as efficient tridentate N,O,S‐donor‐atom ligands for the fac ‐[M(CO) 3 ] + moiety (M= 99m Tc or Re). Reaction of (Et 4 N) 2 [ReBr 3 (CO) 3 ] ( 3 ) with the model S ‐benzyl‐ L ‐cysteine ( 2 ) leads to the formation of [Re( 2′ )(CO) 3 ] ( 4 ) as the exclusive product ( 2′ =C‐terminal anion of 2 ). The tridentate nature of the alkylated cysteine in 4 was established by X‐ray crystallography. Compound 2 reacts with [ 99m Tc(OH 2 ) 3 (CO) 3 ] + under mild conditions (10 −4 M , 50°, 30 min) to afford [ 99m Tc( 2′ )(CO) 3 ] ( 5 ) and represents, therefore, an efficient chelator for the labelling of biomolecules. L ‐Cysteine, S ‐alkylated with a 3‐aminopropyl group (→ 7 ), was conjugated via a peptide coupling sequence with Coα ‐[ α ‐(5,6‐dimethyl‐1 H ‐benzimidazolyl)]‐ Coβ ‐cyanocobamic b ‐acid ( 6 ), the b ‐acid of cyanocob(III)alamin (vitamin B 12 ) ( Scheme 3 ). More convenient was a one‐pot procedure with a derivative of vitamin B 12 comprising a free amine group at the b ‐position. This amine 15 was treated with NHS ( N ‐hydroxysuccinimide)‐activated 1‐iodoacetic acid 14 to introduce an I‐substituent in vitamin B 12 . Subsequent addition of unprotected L ‐cysteine resulted in nucleophilic displacement of the I‐atom by the S ‐substituent, affording the vitamin B 12 alkylated cysteine fragment 17 ( Scheme 4 ). The procedure was quantitative and did not require purification of intermediates. Both cobalamin–cysteine conjugates could be efficiently labelled with [ 99m Tc(OH 2 ) 3 (CO) 3 ] + ( 1 ) under conditions identical to those of the model complex 5 . Biodistribution studies of the cobalamin conjugates in mice bearing B10‐F16 melanoma tumors showed a tumor uptake of 8.1±0.6% and 4.4±0.5% injected dose per gram of tumor tissue after 4 h and 24 h, respectively ( Table 1 ).