The PN(2)S chelate N-[N-(3-diphenylphosphinopropionyl)glycyl]-S-tritylcysteine methyl ester [PN(2)S(Trt)-OMe] was synthesized and reacted with ReOCl(3)(PPh(3))(2) and Ph(4)P[ReOCl(4)]. The reactions of both tritylated and detritylated ligands with Re(V)O precursors gave two diastereomers, 9a and 9b, of the ReO(PN(2)S-OMe) complex. The two isomers, produced in a 1:1 molar ratio, are stable and do not interconvert. They were separated by reverse-phase HPLC and characterized by NMR, FT-IR, and UV-visible spectroscopy and electrospray mass spectrometry. X-ray analysis established for 9a the presence in the solid of the syn isomer. Compound 9a, C(21)H(23)N(2)O(5)PSRe, crystallized from warm acetonitrile in the triclinic space group Ponemacr;, a = 9.828(2) A, b = 11.163(2) A, c = 11.641(2) A, alpha = 106.48(3) degrees, beta = 109.06(3) degrees, gamma = 102.81(3) degrees, V = 1085.7(4) A(3), Z = 2. The PN(2)S coordination set is in the equatorial plane, and the complex shows a distorted square pyramidal coordination. The anti configuration assigned to 9b is consistent with all the available physicochemical data. Follow-up of the reaction of the detritylated ligand with Ph(4)P[ReOCl(4)] in ethanol or acetonitrile indicated that the phosphorus atom of the chelate binds first to the metal and that this bond acts as the driving force for coordination.
Cholecystokinin (CCK) receptors of the subtype B (CCK-BR) have been shown to be overexpressed in certain neuroendocrine tumors including medullary thyroid cancer. Our recent work has focused on new methods to radiolabel the CCK8 peptide with 111In or 99mTc for CCK-B receptor imaging. Derivatives of CCK8 were obtained by addition at the N-terminus in solid phase of a DTPA derivative (DTPAGlu) linked through a glycine spacer (DTPAGlu-G-CCK8) or cysteine, glycine and a diphenylphosphinopropionyl moiety (PhosGC-CCK8) for labeling with 111In and 99mTc, respectively. CCK-BR overexpressing A431 cancer cell lines were utilized to characterize in vitro properties of the two compounds as well as for generating xenografts in nude mice for in vivo characterization. Both 111In-DTPAGlu-G-CCK8 and 99mTcPhosGC-CCK8 showed similar binding affinities for CCK-BR with dissociation constants of 20-40 nM, were internalized after interaction with the receptor and displayed prolonged cellular retention times. Specific in vivo interaction with the receptor of both CCK8 analogs was observed in our animal model. 111In-DTPAGlu-G-CCK8 showed better target to non-target ratios, although it appeared to be rapidly metabolized after injection and activity cleared through the kidneys. 99mTc-PhosGC-CCK8 was more stable in vivo but showed marked hepatobiliary clearance with resulting high background activity in the bowel. The rapid clearance and lower background obtained with 111In-DTPAGlu-G-CCK8 make this a better candidate for further development.
A novel CCK8 derivative bearing a chelating agent at its N- end and its oxo-rhenium(V) complex have been synthesized and characterized. The chelating agent N-[N-13-(diphenylphosphino)propionyl]glycyl]cysteine (PN2S) ligand, the coordination set of which is made by the phosphorus atom of phosphine, the nitrogen atoms of the two amido groups and the sulphur atom of cysteine, has been used due to its high affinity towards the oxo-rhenium(V) moiety. Molecular modelling studies indicate that the CCK8 peptide adopts the right conformation for cholecystokinin receptor binding, and that modifications on the N-terminal side of CCK8 obtained by introducing chelating agents and its metal complexes should not affect the interaction with CCK(A) receptor.
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