Rhenium(V) and Technetium(V) Oxo Complexes of an N₂N‘S Peptidic Chelator:  Evidence of Interconversion between theSynandAntiConformations

Abstract

Neutral Re(V) and Tc(V) oxo complexes of the peptide dimethylglycyl-L-seryl-L-cysteinylglycinamide (RP294) were prepared and characterized by HPLC, spectroscopic techniques, and X-ray crystallographic analysis. The peptide was prepared as a single peptide chain using solid phase methods and characterized by HPLC and various spectroscopic techniques. The water-soluble Re(V) oxo complex of dimethylglycyl-L-seryl-L-cysteinylglycinamide [ReO(RP294)] was prepared from the reaction of the peptide with either [ReO(2)(en)(2)]Cl or ReOCl(3)(PPh(3))(2) in the presence of base. The complex exists as two isomers, the serine CH(2)OH group being in the syn oranti conformation with respect to the Re-oxo bond. The ratio of the isomers at room temperature is 1:1.1. The isomers were separated by reverse-phase HPLC, but the isolation of each isomer was complicated by their rapid interconversion in aqueous solution at room temperature. The molecular structure of the syn isomer of the Re complex was determined by X-ray crystallography. Crystals of syn-[ReO(RP294)] (C(12)H(20)N(6)O(5)ReS) are orthorhombic, of space group P2(1)2(1)2(1), with a = 6.954(1) Å, b = 8.0472(1) Å, c = 32.9183(4) Å, and Z = 4. The structure was solved by direct methods and was refined by full-matrix least-squares procedures to R = 0.0327 (R(w) = 0.0838) for 10 447 reflections with I > 2sigma(I). The Re metal was coordinated in a distorted square pyramidal geometry with the oxo moiety in the apical position. The peptide coordinated to ReO(3+) via the N(amine) atom of dimethylglycine, the S(thiolate) atom of cysteine, and the two N(amide) atoms of serine and cysteine (an N(2)N'S donor atom set). The Re atom lies approximately 0.74 Å above the distorted plane formed by the N(2)N'S donor atom set. Variable-pH (1)H NMR spectral data showed the Re complex was stable from pH 5 to 8.5. The reaction of (99)TcO(4)(-) with SnCl(2), sodium gluconate, and RP294 produced the (99)Tc(V) oxo RP294 complex, [(99)TcO(RP294)]. Like the [ReO(RP294)] complex, [(99)TcO(RP294)] also exists in the syn and anti conformations in a ratio of approximately 1:1. The (99m)Tc complex of RP294 was prepared at the tracer level from the reaction of Na[(99m)TcO(4)] with excess SnCl(2), sodium gluconate, and RP294. The (99m)Tc and Re RP294 complexes behaved similarly under identical HPLC conditions.

Complexes of an Alpha Thymosin Derivative with 185/187Re and 99mTc: Structural Analysis and Initial Biological Evaluation

“…As observed in the literature for ReO(V) 3+ complexes with the same N,N-dimethylGly1¢-Ser2¢-Cys3¢ tripeptide chelator (25,31), the syn-isomer eluted first. Isolation of each species was not possible since in HPLC fractions enriched in one isomer the equilibrium ratio of syn ⁄ anti 3:2 would quickly re-establish, apparently through isomer interconversion as previously reported (25,30,31). The same HPLC gradient was applied in the analysis of the 99m Tc-1 complex and also in this case the syn-and anti-isomers were observed in a 3:2 ratio (Figure 6) having t R values similar to those of the 185 ⁄ 187 Re-1 analog.…”

“…The specific N,N-dimethylglycyl-L-seryl-L-cysteinyl tripeptide sequence employed in this work has been evaluated as a MO(V) 3+ (M = Re, Tc) chelator (25,31,35,36), and the formation of syn ⁄ anti-diastereomers is reported, typically in a 1:1 ratio. In our case, the prevalence of the syn-isomer over the anti-isomer which apparently reflects a slightly greater stability of the syn-isomer over the anti-isomer, can only be attributed to the specific characteristics of the side chain attached on the aC of Cys3¢.…”

“…In our case, the prevalence of the syn-isomer over the anti-isomer which apparently reflects a slightly greater stability of the syn-isomer over the anti-isomer, can only be attributed to the specific characteristics of the side chain attached on the aC of Cys3¢. Differentiation of the two isomers in the NMR spectra was based on comparison with coupling constants and chemical shifts of the aCH and bCH 2 protons of Cys3¢ to those reported for similar complexes of known configuration (25,30).…”

“…Upon coordination of the N,N-dimethylGly1¢-Ser2¢-Cys3¢ sequence consisting of L-amino acids, formation of two diastereomers is theoretically possible depending on the orientation of the side chain of Ser2¢ relative to the oxygen of the ReO(V) 3+ core ( Figure 2B): in the syn-configuration the side chain and the oxygen point in the same direction, while in the anti-configuration they point to opposite directions. Comparison of the chemical shift differentiation of the bCH 2 protons and of the coupling constants between the aCH and the bCH 2 protons of the Cys3¢ residue to those reported for similar ReO complexes with known configuration (25), allowed the distinction of the…”

Evaluation of ανβ3-Mediated Tumor Expression with a 99mTc-Labeled Ornithine-Modified RGD Derivative During Glioblastoma Growth In Vivo

“…35 As far as the tri-amino acid spacer of ornithines might be concerned, by maximizing the effect of the charge with the introduction of this polar linker, the hydrophilic character of the final compound influenced the targeting efficiency of a m b 3 integrin receptors and the overall biodistribution profile. More specifically, c(RGDfK)-(Orn) 3 -[CGG-…”