S‐Functionalized Cysteine: Powerful Ligands for the Labelling of Bioactive Molecules with Triaquatricarbonyltechnetium‐99m(1+) ([^99mTc(OH₂)₃(CO)₃]⁺)

Abstract

S‐Alkylated cysteines are used as efficient tridentate N,O,S‐donor‐atom ligands for the fac‐[M(CO)3]+ moiety (M=99mTc or Re). Reaction of (Et4N)2[ReBr3(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 [99mTc(OH2)3(CO)3]+ under mild conditions (10−4 M, 50°, 30 min) to afford [99mTc(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‐1H‐benzimidazolyl)]‐Coβ‐cyanocobamic b‐acid (6), the b‐acid of cyanocob(III)alamin (vitamin B12) (Scheme 3). More convenient was a one‐pot procedure with a derivative of vitamin B12 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 B12. Subsequent addition of unprotected L‐cysteine resulted in nucleophilic displacement of the I‐atom by the S‐substituent, affording the vitamin B12 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 [99mTc(OH2)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).

99mTcI/ReI Tricarbonyl Complexes with Tridentate Cysteamine Based Ligands: Synthesis, Characterization and in vitro/in vivo Evaluation

“…99m Tc(CO) 3 ] + core, [9][10][11][12] in contrast to related linear/tridentate ligands that have the same donor atom set. Nevertheless, the different topologies of structurally related chelators (e.g.…”

“…The Re-C, Re-O, Re-N, and Re-S bond lengths found for 1 are comparable to those reported for other octahedral complexes containing the fac-[Re(CO) 3 ] + unit and the same donor atoms. [9][10][11][12]21] …”

Functionalised Tris(pyrazolyl)methane Ligands and Re(CO)3 Complexes Thereof

“…[1][2][3] Several groups are developing ligands for the radio-labelling of bio-molecules. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] Many of these ligating moieties are based upon bis(pyridylmethyl)amine derivatives and we have also developed a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer with bis(pyridylmethyl)amine derivatives as metal binding sites. [19] Another class of widely used ligands in coordination chemistry and organometallic chemistry are the tris(pyrazolyl)borates (Tp), developed by Trofimenko in the early sixties.…”

Tricarbonyltechnetium(I) and tricarbonylrhenium(I) complexed with N-methyl-2-pyridinecarboxyamide as potential radiopharmaceuticals: a computational study

“…According to the reaction scheme proposed by Alberto [37], coupling of cysteine to a [ 99m Tc(OH 2 ) 3 (CO) 3 ] ? aquocomplex leaves the CO ligands intact, whereas three other bonds to the metal are formed due to chelation by a tridentate O,S,N ligand.…”