S-Functionalized Cysteine: Powerful Ligands for the Labelling of Bioactive Molecules with Triaquatricarbonyltechnetium-99m(1+) ([99mTc(OH2)3(CO)3]+)
✍ Scribed by Dave R. van Staveren; Paul D. Benny; Robert Waibel; Philipp Kurz; Jae-Kyoung Pak; Roger Alberto
- Publisher
- John Wiley and Sons
- Year
- 2005
- Tongue
- German
- Weight
- 161 KB
- Volume
- 88
- Category
- Article
- ISSN
- 0018-019X
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✦ Synopsis
Abstract
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).