Synthesis of ^99mTc and ¹⁸⁸Re complexes of N₃S and N₂S₂ amide mercaptide esters: Effect of side chain length on yield and proposed mechanism

Abstract

The inorganic chemistry of diamide dimercaptide (N S ) and triamide mercaptide (N S ) complexes of techn have been extensively ztudied using carrier "Tc and cold r nium because of the renal excretion imaging properties of their '5mTc analog. Indeed, we reported the crystal structures of the rhenium complex of mercaptoacetylglycylglycy~glycinate [Re(V)-MAG ] along with the syn epimer of the rhenium complex of 4, S-dithioa2etamidopropanoate [Re(V)-C N2S2] while the structure of [Tc(V)-MAG3] was a120 reported (1,2).Application of these ligand systems ( Figure 1) offered advantages for the labeling of proteins, particularly monoclonal antibodies, because of (a) the excellent stability of amide mercaptide complexes in a wide range of pH and temperatures, (b) their well delineated chemistry, and (c) the lack of metal core interaction with functional groups that could be further derivatized for protein conjugative labeling. Practical application of the preformed chelate approach (PFC), required chelation of ligand bearing active ester for subsequent conjugation &gmprotein lysine groups. The preparation and characterization of Tc-4,5-dithioacetamidopentanoate, and in particular, its tetrafluorophenyl ester (C5N2S2-TFP) was demonstrated and presented (3).However, the reasons that led to the choice of that particular ligand system were not obvious. The labeling data u34;g carbodiimide (CDI) condensation of the appropriate Tc complex with TFP (Scheme 1 ) showed that, by increasing the side chain length bearing the carboxylate, the yields of the TFP active ester were increased from less than25% with the propanoate based ligand ( C N S 2 ) or MAG ani $he N3S syszems (Table 1). Transchelation relagei results were obtained when the TFP ester complexes were formed from the "'Tc-gluconate or Re-citrate ( Table 2). In these instances, the yields of complexes were only high for the C N S 2 and the mercaptoacetylglycylglycyl-gamma aminobutyrate (&d2-GABA) ligands, while practically negligable for the others. The other products were the carboxylate form of the complexes.Similarly, the ester yield was very low (~2 % ) when glycine adduct of C3N2S2-TFP was attempted for labeling with Tc-gluconate. The major product formed was the carboxylate form of the glycine adduct.ium in6 rhenium to greater than 70% in both the N S ropriate ligand-ygg ester by direct ligand exchange using eitherThe basis for the poor yields was attributed to competing hydrolysis of the TFP ester group during the transchelation step. A review of the structure of .the ligands studied show that four of them (C3 and C4-N2S2, MAG and MAG2-ala) can form five 3

Bifunctional chelators for radiorhenium: past, present and future outlook

“…4a). 71,72 This was later replaced with the S-benzoyl-MAG 3 chelator (Fig. 4b), which was first radiolabelled with 186 Re in 1993 and continues to be used today as an effective way of producing 186/188 Re-MAG 3 .…”

“…23 Although the 99m Tc-MAG 3 complex is stable, the MAG 3 chelator, used as is, produced very low complex yields when coordinated to radiorhenium. 71 As a result, in 1989 the MAG 2 -GABA (MAG 2 -γ-aminobutyrate) chelator, modified from MAG 3 , became the first N 3 S BFC for radiorhenium preconjugation labelling of antibodies (Fig. 4a).…”