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

Autor: Jae-Kyoung Pak, Paul Benny, Roger Alberto, Robert Waibel, Dave R. van Staveren, Philipp Kurz
Rok vydání: 2005
Předmět:
Zdroj: Helvetica Chimica Acta. 88:447-460
ISSN: 1522-2675
0018-019X
DOI: 10.1002/hlca.200590029
Popis: 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 (10−4M, 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).
Databáze: OpenAIRE
Externí odkaz: