Solid state catalytic tritiation: Isotopic exchange and tritium addition in high specific activity synthesis

Solid state catalytic saturation of double bond with hydrogen, deuterium and tritium is a valid route to incorporate selectively isotopes in specific positions. We studied the best fitting of all parameters that rule the radioactive yield of tritiation of an unsatured substrate, to guarantee the maximum incorporation of labeled atom in the product at room temperature. The wise choice of experimental parameters allowed very high radiochemical yields. The number of tritium exceeded the statistical presence of two atoms. Relative magnitudes for addition and exchange kinetic constants are provided.     

Serotonin receptor agonists buspirone and (+/−)-DOB: Tritiation at high specific activity

Serotonergic agonists buspirone 1 and (+/–)-DOB 4 have been labeled with tritium at high specific activity and have emerged as valuable tools to study the serotonin receptor family.This revised version was published online in November 2005 with corrections to the Cover Date.     

Synthesis of tritiated antiviral isoxazoles at high specific activity

The tritiation of WIN 51711 and several structural analogues is described.     

Synthesis of some 6-keto morphinan mu opiate receptor agonists labelled with tritium at high specific activity

The high specific activity tritiation of oxymorphone and pentamorphone is described.     

The endogenous GABA analogue gamma-hydroxybutyric acid: Tritium labeling at high specific activity

2,3,4-³H] Gamma-hydroxybutyric acid (GHB, 4) was prepared by means of a catalytic tritium reduction of 2(5H)-furanone (2) followed by hydrolysis. It has proven useful as a tool to study the GHB receptor. This revised version was published online in July 2006 with corrections to the Cover Date.     

Tritium labelling of several cancer pathway agents at high specific activity

The tritiation of benzo[a]pyrene and phorbol-12,13-dibutyrate is described.     

Tritiation of several intrinsically activated photoaffinity agents at high specific activity

The tritiation of natural photoffinity ligands chlorpromazine and cytochalasin B is described.     

Intermolecular hydroacylation: high activity rhodium catalysts containing small-bite-angle diphosphine ligands

Readily prepared and bench-stable rhodium complexes containing methylene bridged diphosphine ligands, viz. [Rh(C(6)H(5)F)(R(2)PCH(2)PR'(2))][BAr(F)(4)] (R, R' = (t)Bu or Cy; Ar(F) = C(6)H(3)-3,5-(CF(3))(2)), are shown to be practical and very efficient precatalysts for the intermolecular hydroacylation of a wide variety of unactivated alkenes and alkynes with β-S-substituted aldehydes. Intermediate acyl hydride complexes [Rh((t)Bu(2)PCH(2)P(t)Bu(2))H{κ(2)(S,C)-SMe(C(6)H(4)CO)}(L)](+) (L = acetone, MeCN, [NCCH(2)BF(3)](-)) and the decarbonylation product [Rh((t)Bu(2)PCH(2)P(t)Bu(2))(CO)(SMePh)](+) have been characterized in solution and by X-ray crystallography from stoichiometric reactions employing 2-(methylthio)benzaldehdye. Analogous complexes with the phosphine 2-(diphenylphosphino)benzaldehyde are also reported. Studies indicate that through judicious choice of solvent and catalyst/substrate concentration, both decarbonylation and productive hydroacylation can be tuned to such an extent that very low catalyst loadings (0.1 mol %) and turnover frequencies of greater than 300 h(-1) can be achieved. The mechanism of catalysis has been further probed by KIE and deuterium labeling experiments. Combined with the stoichiometric studies, a mechanism is proposed in which both oxidative addition of the aldehyde to give an acyl hydride and insertion of the hydride into the alkene are reversible, with the latter occurring to give both linear and branched alkyl intermediates, although reductive elimination for the linear isomer is suggested to have a considerably lower barrier.     

Isolation of 57Co-cobalamin coenzymes at high specific activity from Streptomyces griseus.

The distribution of radio-labelled cobalamins in Streptomyces griseus grown in medium containing 57Co-cobalt chloride has been estimated by two-dimensional thin-layer chromatography and bioautography. 57Co-Methylocobalamin (Me[57Co]Cbl) was the major form in the mycelium together with smaller amounts of 57Co-adenosylcobalamin (Ado[57Co]Cbl) and 57Co-hydroxocobalamin (OH[57Co]Cbl). The OH[57Co]Cbl was detected in three forms having, respectively, anionic, cationic and neutral properties. A simple technique has been developed to isolate and purify Me[57Co]Cbl and Ado[57Co]Cbl from the mycelium using column chromatography on ion-exchange celluloses. Small quantities of each cobalamin coenzyme have been obtained at 90--96% purity and specific activities of 190--230 muCi/microgram.     

Synthesis and pharmacological analysis of high affinity melatonin receptor ligands

We report the synthesis and radioligand binding analysis of a series of naphthalenic melatonin receptor ligands, N-[2-(7-alkoxy-2-methoxy-1-naphthyl)ethyl]propionamide. This series of ligands exhibits subpicomolar binding affinity to both MT1 and MT2 melatonin receptors expressed in chinese hamster ovary (CHO) cells.     

Lipopeptides incorporated into supported phospholipid monolayers have high specific activity at low incorporation levels

The ability to present cell adhesion molecule (CAM) ligands in controlled amounts on a culture surface would greatly facilitate the control of cell growth and differentiation. Supported lipid monolayer/bilayer systems have previously been developed that allow for presentation of CAM ligands for cell interaction; however, these systems have employed peptide loadings much higher than those used in poly(ethylene glycol) (PEG)-based immobilization systems. We report the development of synthetic methods that can be used for the efficient and versatile creation of many linear and cyclic lipid-linked peptide moieties. Using RGD-based peptides for the alpha5beta1 integrin as a model system, we have demonstrated that these lipopeptides support efficient cell binding and spreading at CAM ligand loadings as low as 0.1 mol %, which is well below that previously reported for supported lipid systems. Engineered lipopeptide-based surfaces offer unique presentation options not possible with other immobilization systems, and the high activity at low loadings we have shown here may be extremely useful in presenting multiple CAM ligands for studying cell growth, differentiation, and signaling.     

Diironhexacarbonyl clusters with imide and amine ligands: hydrogen evolution catalysts

The reaction of Fe₃(CO)₁₂ and N-(4-thiolphenyl)-1,8-naphthalimide afforded a new diironhexacarbonyl complex (3). The integrity and electronic structure of 3 has been determined by elemental analysis and spectroscopy (NMR and infrared). Infrared spectrum of 3 shows peaks at 2000, 2040, and 2075?cm^?1 ascribed to stretching frequencies of the terminal metal carbonyls. Compound 4 was obtained from the reaction of Fe₃(CO)₁₂ and 4-aminothiolphenol. A comparison of the electronic, electrochemical, and electrocatalytic properties of 3 and 4 are discussed. Cyclic voltammetric studies show that 3 and 4 catalyze the reduction of acetic acid to produce hydrogen at ?2.19?V and ?1.88?V versus Fc/Fc⁺, respectively.     

Structure elucidation of two tryptophan-derived, high affinity Ah receptor ligands

Background: Environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other structurally related ‘environmental hormones’, exert their harmful biological effects through the Ah receptor signaling pathway. Several naturally occurring substances also bind to this receptor, but its natural role is still obscure. Tryptophan derivatives of the indolo[3,2-b]carbazole type, earlier suggested by us to be endogenous ligands for the receptor, should be a powerful tool in understanding receptor function. We therefore: set out to determine their identity.Results: The two tryptophan-derived Ah receptor ligands have been chemically analyzed and characterized by means of mass spectrometry, ¹H NMR and ¹³C NMR. UV, infra-red and fluorescence spectra were also recorded. All data are in accordance with the two compounds being closely related indolo[3,2-b]carbazole derivatives. Evidence is presented that compound A (MW = 312) is the symmetrical 6,12-diformylindolo[3,2-b]carbazole, and compound B (MW = 284) is the monosubstituted 6-formylindolo[3,2-b]carbazole.Conclusions: The elucidation of the structures of the two high affinity Ah receptor ligands 6,12-diformylindolo[3,2-b]carbazole and 6-formylindolo[3,2-b]carbazole provides the necessary basis for further mechanistic studies of this important group of compounds, and will help in determining the natural role of the Ah receptor.     

Preparation of high specific activity radiotracers for radioanalytical studies

High specific activity radiotracers are very suitable for studies related to the toxicological impact of trace elements onto human health. In order to investigate the metabolic behaviour of Low Level Exposure (LLE) to trace elements, it is necessary to carry out in-vitro and in-vivo experiments with tracers whose concentration is of the same order of magnitude as the present environmental exposure values (ng-g/kg day). Preparations, separations and purifications of some No Carrier Added (NCA) radiotracers (⁴⁸V,^95m,96Tc,^{195m,g,197m,g}Hg,¹⁹⁹Au,²⁰²Tl) produced by either cyclotron or nuclear reactor irradiation, are presented and discussed. This work reviews the more recent advances in this field carried out by our groups.     

Macrobicyclic cage amine ligands for copper radiopharmaceuticals: a single bivalent cage amine containing two Lys3-bombesin targeting peptides

The synthesis of new cage amine macrobicyclic ligands with pendent carboxylate functional groups designed for application in copper radiopharmaceuticals is described. Reaction of [Cu((NH(2))(2)sar)](2+) (sar = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane) with either succinic or glutaric anhydride results in selective acylation of the primary amine atoms of [Cu((NH(2))(2)sar)](2+) to give derivatives with either one or two aliphatic carboxylate functional groups separated from the cage amine framework by either a four- or five-atom linker. The Cu(II) serves to protect the secondary amine nitrogen atoms from acylation, and can be removed to give the free ligands. The newly appended carboxylate functional groups can be used as sites of attachment for cancer-targeting peptides such as Lys(3)-bombesin. The synthesis of the first dimeric sarcophagine-peptide conjugate, possessing two Lys(3)-bombesin peptides tethered to a single cage amine, is presented. This species has been radiolabeled with copper-64 at ambient temperature and there is minimal dissociation of Cu(II) from the conjugate even after two days of incubation in human serum.     

High specific activity tritium labelling of some sigma-1 receptor agonists

The high specific activity tritiation of (+)-SKF-10,047 (1) and N,N-dimethyltryptamine (4) is described. [N-allyl-³H] (+)-SKF-10,047 (3) was prepared by Lindlar catalyst tritiation of (+)-N-propargylnormetazocine (2) and [N-methyl-³H] N,N-dimethyltryptamine (6) was synthesized by the alkylation of N-methyltryptamine (5) with [³H] methyl iodide. Both sigma-1 synthetic agonist 3 and endogenous agonist 6 have been useful in studying this receptor.     

Trans titanium(IV) complexes of salen ligands exhibit high antitumor activity

Salen-titanium(IV) complexes are introduced as a new family of highly efficient antitumor complexes, being the first cytotoxic titanium(IV) complexes of trans labile ligands, as characterized crystallographically. Four complexes with different aromatic substitutions were analyzed, reveling a meaningful effect of the ligand structure on the complex performance. All complexes exhibit high hydrolytic stability, where the labile OAr ligands hydrolyze in a 10% D(2)O solution with t(1/2) ranging from 2 to 11 h. The IC(50) values obtained for three of the salen complexes studied on HT-29 colon and OVCAR-1 ovarian cells demonstrate activity that exceeds those of the known tianium(IV) complexes Cp(2)TiCl(2) and (bzac)(2)Ti(OiPr)(2) and that of cisplatin, where the most active para-chlorinated complex exhibits activity enhancement relative to cisplatin by 10-fold.     

Electrochemical method for producing radionuclide Lu-177 with high specific activity

A modified method for the isolation of radionuclide ¹⁷⁷Lu obtained from a Yb-176 target irradiated with thermal neutrons is proposed. The method consists of the combination of two electrochemical processes— cementation of ytterbium acetate–chloride solution to sodium amalgam and subsequent electrolysis of the ytterbium solution in a separate electrolytic cell without adjusting the solution. The electrochemical setup consisting of two cells gives the purification factor of ¹⁷⁷Lu from ytterbium at a level of 10⁵–10⁶, which allows using ¹⁷⁷Lu of such quality for labeling bioorganic molecules.     

A simple method for preparation of high specific activity128I

The preparation of high specific activity¹²⁸I by neutron activation of KIO₃ is described. The¹²⁸I^– produced in a Szilard-Chalmers process is eluted with a water-isopropylamine mixture which dissolves only KI but not KIO₃.