MO tripeptide diastereomers (M=99/99mTc, Re): models to identify the structure of 99mTc peptide targeted radiopharmaceuticals

Biologically active molecules, such as many peptides, serve as targeting vectors for radiopharmaceuticals based on 99mTc. Tripeptides can be suitable chelates and are easily and conveniently synthesized and linked to peptide targeting vectors through solid-phase peptide synthesis and form stable TcVO complexes. Upon complexation with [TcO]3+, two products form; these are syn and anti diastereomers, and they often have different biological behavior. This is the case with the approved radiopharmaceutical [99mTcO]depreotide ([99mTcO]P829, NeoTect) that is used to image lung cancer. [99mTcO]depreotide indeed exhibits two product peaks in its HPLC profile, but assignment of the product peaks to the diastereomers has proven to be difficult because the metal peptide complex is difficult to crystallize for structural analysis. In this study, we isolated diastereomers of [99TcO] and [ReO] complexes of several tripeptide ligands that model the metal chelator region of [99mTcO]depreotide. Using X-ray crystallography, we observed that the early eluting peak (A) corresponds to the anti diastereomer, where the Tc=O group is on the opposite side of the plane formed by the ligand backbone relative to the pendant groups of the tripeptide ligand, and the later eluting peak (B) corresponds to the syn diastereomer, where the Tc=O group is on the same side of the plane as the residues of the tripeptide. 1H NMR and circular dichroism (CD) spectroscopy report on the metal environment and prove to be diagnostic for syn or anti diastereomers, and we identified characteristic features from these techniques that can be used to assign the diastereomer profile in 99mTc peptide radiopharmaceuticals like [99mTcO]depreotide and in 188Re peptide radiotherapeutic agents. Crystallography, potentiometric titration, and NMR results presented insights into the chemistry occurring under physiological conditions. The tripeptide complexes where lysine is the second amino acid crystallized in a deprotonated metallo-amide form, possessing a short N1-M bond. The pKa measurements of the N1 amine (pKa approximately 5.6) suggested that this amine is rendered more acidic by both metal complexation and the presence of the lysine residue. Furthermore, peptide chelators incorporating a lysine (like the chelator of [TcO]depreotide) likely exist in the deprotonated form in vivo, comprising a neutral metal center. Deprotonation possibly mediates the interconversion process between the syn and anti diastereomers. The N1 amine group on non-lysine-containing metallopeptides is not as acidic (pKa approximately 6.8) and does not deprotonate and crystallize as do the metallo-amide species. Three of the tripeptide ligands (FGC, FSC, and FKC) were radiolabeled with 99mTc, and the individual syn and anti isomers were isolated for biodistribution studies in normal female nude mice. The main organs of uptake were the liver, intestines, and kidneys, with the FGC compounds exhibiting the highest liver uptake. In comparing the diastereomers, the syn compounds had substantially higher organ uptake and slower blood clearance than the anti compounds.     

Menschlicheα 1-GIycoproteine. Abtrennung aus pathologischem Urin und Untersuchung durch immunologische und elektrophoretische Methoden

Ohne Zusammenfassung     

The synthesis of 1β(H), 6β(Me)-2,2,6-trimethyl-8-ethylbicyclo-[4,3,0]-7-thianonane and the structure of the isomeric bicyclic-terpenoid sulfides occurring in petroleum.

The synthesis of the title compound is described. Comparison of ms and nmr data with those of the isomeric bicyclic terpenoid sulfide of petroleum shows that the latter has the structure of 1α(H), 6β(H)-2,2-dimethyl-9-ethylbicyclo-[4,4,0]-8-thiadecane.     

A Versatile and Efficient Hydrosilylation Route to Functionalized Polyferrocenylsilanes

Summary: The synthesis of a series of polyferrocenylsilanes (PFSs) containing CC functionalities in the side‐group structure and their subsequent derivatization by hydrosilylation chemistry are described. Hydrosilylation is shown to be an effective postpolymerization functionalization method, particularly in the case of poly(ferrocenylmethylvinylsilane), which can be prepared by photolytic anionic ring‐opening polymerization of the corresponding ferrocenophane monomer.

     

Infinite idempotent quasi-affine algebras need not be hereditarily absorption free

It is known that for finite algebras, solvable implies hereditarily absorption free. We present an example which shows that this implication does not hold for infinite algebras. This example is also quasi-affine, contradicting an earlier statement that quasi-affine algebras are hereditarily absorption free.     

Pyrones VII. An Efficient Preparation and the Selective Reduction of Methyl 2,6-Dimethyl-4H-Pyran-4-one-3-Carboxylate

The syntheses of 4H-pyran-4-one-3-carboxylic acids and derivatives which have been previously reported (for example, starting with ketene¹, diketene², or dehydroacetic acid³) normally proceed only in low yield, often requiring rigorous control of the reaction conditions. We have shown that the reaction of dehydroacetic acid (1) with “magic methyl” (methyl fluorosulfonate) produces methyl 2,6-dimethyl-4H-pyran-4-one-3-carboxylate (4) in high yield (85%) under mild conditions.     

N.M.R. gas to dilute solution chemical shifts for hexafluorobenzene

Studies of ¹H, ¹³C, ¹²⁵Te, ¹²³Te relaxation rates in liquid dimethyltelluride were carried out. Relaxation mechanisms have been separated for all four studied nuclei. Tellurium relaxation was found to be strictly dominated by spin rotation, while for ¹H and ¹³C, dipole-dipole and spin rotation interactions exist simultaneously. Reorientation of methyl groups about their symmetry axis was found to be approximatively of the same rate as the overall molecular motion.     

9‐Silafluorenyl Dichlorides as Chemically Ligating Coupling Agents and Their Application in Peptide Synthesis

A fundamentally simple, mild, and practical procedure for peptide bond formation is reported that employs a stoichiometric amount of easy‐to‐access 9‐silafluorenyl dichlorides as the coupling agent. Without initial preactivation or elaboration of the carboxylic acid or amine termini of the amino acids, the developed reagent is proposed to act through an unprecedented chemical ligation mechanism, bringing the two coupling partners together before being subsequently eliminated. The desired amides or peptide bonds are thus furnished in good yields and with low to no epimerization.