Vitamin B12 is a biomolecule that is fundamental for most living organisms despite being produced by only a few bacteria. mitochondria, cell nucleus, and cytoplasm. Its uptake in humans is very complex and requires at least three different transport proteins: intrinsic factor (IF), transcobalamin, and haptocorrin. The human organism uses vitamin B12 very efficiently: the daily requirement is only about 10 mg. Its chemistry, biochemistry, and biology has been comprehen-sively reviewed. [1–4] The demand for vitamin B12 (abbreviated as "B12") is concentrated at sites of enhanced proliferation, in particular in cancer cells or at sites of bacterial infections. An organisms need for B12 makes it an attractive targeting agent. Appli-cations of B12 to the delivery of radioisotopes [5, 6] or as various cytotoxic agents to cancer cells, for which it can be used as a Trojan horse, have been the most actively studied areas of research. [7–9] Both of these strategies require derivatization of B12, and so the introduction of ligands or receptor-binding molecules has been reported. [5,6, 9, 10] Chelators for radiometals have been conjugated to peripheral acid groups (prepared by controlled amide hydrolysis) and coordinated to the 5'-OH group in the ribose ring of the backloop. Alternatively, a Co III center can be reduced to Co I and a molecule introduced by oxidative alkylation. [8, 11] The only functionality in B12 that has not received much attention is the Co III -coordinated cyanide group. It is well established that MÀCN moieties tend to bridge two metal centers to form a M-C-N-M' unit. Numerous examples have been published and reviewed to date, [11] but examples with porphyrin-like systems are rare [12–14] and, to the best of our knowledge, unknown for B12. The reverse situation in which [Fe(CN) 6 ] 3À or nitroprusside [Fe(NO)(CN) 5 ] À are coordi-nated to Co III or Co II centers of aqua–cobalamin has been studied in detail. [15–19] It is intriguing to use the cyanide anion in B12 as a ligand and to introduce a metal complex either by direct coordina-tion to B12 or by conjugation of an organic molecule through mediation by a metal complex (pathways 1 and 2 in Scheme 1). Since Co-CN-M' is not very stable, M' represents an inert complex fragment. Our interest lies in radiopharmaceuticals containing the fac-[ 99m Tc(CO) 3 ] + moiety. [20–22] The water ligands are readily exchanged in [ 99m Tc(OH 2) 3 (CO) 3 ] + , to yield complexes of high kinetic stability even with monodentate donors. [23] The concept of our study involved B12 acting as a monodentate ligand while the other two sites of fac-[M(CO) 3 ] + are bound to a bidentate ligand L 2 . The complex [ 99m Tc(OH 2)(L 2)(CO) 3 ] is then coordinated to B12. The ligand L 2 , introduced prior to B12 coordination, is variable and allows the biological authenticity of the final conjugate to be fine-tuned. The use of a bidentate and a monodentate ligand on the fac-[ 99m Tc(CO) 3 ] + moiety is consistent with a mixed ligand approach. [24] The reaction of [M(OH 2) 3 (CO) 3 ] + (M = 99 Tc, 1; Re, 2) in water with the monoanionic ligands (L 2), imidazolecarboxylic acid (Himc), picolinic acid (Hpic), 2,4-dipicolinic acid (Hdipic) or serine (Hser), and N,N-dimethylglycine (Hdmg) yields [M(L 2)(OH 2)(CO) 3 ]. The corresponding 99m Tc com-plexes are prepared directly from [ 99m TcO 4 ] À . The bidentate ligand is tightly bound but the remaining water ligand can be replaced by the nitrogen atom from the cyanide anion in B12. [M(L 2)(OH 2)(CO) 3 ] exhibits a strong affinity for imidazole-type ligands but coordination to intermediately released benzimidazole from B12 was not observed. The reaction of [Re(imc)(OH 2)(CO) 3 ] (3), [Re(dipic)(OH 2)(CO) 3 ] (4), [Re(ser)(OH 2)(CO) 3 ] (5), [Re(dmg)(OH 2)(CO) 3 ] (6), or their 99m Tc analogues with B12 in methanol or water afforded [(3ÀB12)] (7), [(4ÀB12)] (8), [(5ÀB12)] (9), and [(6ÀB12)] (10). High-performance liquid chromatographic (HPLC) analysis after coordination of Re or 99(m) Tc centers gave only two well-separated signals in a ratio of about 1:1. The comparable retention times from the UV/Vis analysis of, for example, 7 and the corresponding radioactivity trace of the 99m Tc complex indicate the identity of the Re and Tc com-plexes (Figure 1). The signals can be understood by the two possible orientations adopted by the bidentate N,O ligand L 2 relative to the corrin ring ([M(L 2)(OH 2)(CO) 3 ] complexes are racemic) and, thus, the presence of two diastereomers. The