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[3 H]Genipin was synthesized in a single step by Ir(I) catalyzed hydrogen isotope exchange. Conditions for selective exchange of the sp2 CH bond ortho to the methyl ester functionality were developed through deuterium modeling studies through a catalyst screen. Optimized conditions so obtained were then utilized with tritium gas to generate [3 H]genipin at a specific activity of 18.5 Ci/mmol. Racemic [14 C]genipin was prepared in eight steps in overall 5.4% radiochemical yield from potassium [14 C]cyanide.

The Pacific Northwest National Laboratory operates the Radiochemical Processing Laboratory, which is a multi-purpose, non-reactor nuclear research facility. Regulations require both continuous sampling and monitoring of radioactive particulates and tritium gas in the exhaust from the main stack. Releases of other radioactive gases, including planned releases of radon, are tracked separately in a database and reported. During the 2015 calibration of the Radiochemical Processing Laboratory stack continuous air monitor, measured alpha and beta background count rates were much higher than expected, especially when compared to count rates from previous calibrations. The source of the higher background count rates was examined by trending of historical continuous air monitor measurements and a comparison to the sampler data. The analysis revealed that the sample results showed no increase in emissions, whereas the continuous air monitor showed a steady increase in count rates. Ultimately, the continuous air monitor filter was analyzed and found to contain higher-than-normal background levels of Rn progeny. Assessments were performed to determine the cause of the increased background values, including reviews of building research activities, radioactive material usage and storage, adequacy of procedures, and the potential for internal continuous air monitor contamination. Project reviews determined that a research activity involving Th was left in an unsealed state, resulting in Rn being released from a hot cell into the exhaust system. The Th source material was subsequently repackaged and contained, resulting in a decrease of continuous air monitor background count rates. An estimate of the Rn release was made and the contribution to the annual offsite dose from the facility was calculated. The released activity and reported dose results were well below the permit limits for the facility.

The initial discovery and establishment of a family of novel iridium catalysts possessing N-heterocyclic carbene units alongside bulky phosphine ligands allowed selected substrates to be labelled using deuterium or tritium gas at desirably low catalyst loadings via an ortho-directed C-H insertion process. Such a method has broad applicability and offers distinct advantages within the pharmaceutical industry, directly facilitating the ability to carefully monitor a potential drug molecule’s biological fate. Over the past decade since these initial protocols were divulged, many additional advances have been made in terms of catalyst design and substrate scope. This review describes the broadened array of new iridium catalysts and associated protocols for direct and selective C-H activation and hydrogen isotope insertion within a number of new chemical entities of direct relevance to the pharmaceutical industry.

A solid phase extraction method for removing polar tritiated contaminants from tritium-containing waste oils has been developed. The composition of the degradation products present in the waste oil was determined. The results indicated that upon exposure to tritium gas, fragment methyl ketones, carboxylic acids, and lactones were the main polar products of the mineral-based oil oxidation. The nonpolar fragmentation products included n-alkanes, monomethylalkanes, and acyclic isoprenoids and were analogous to those formed during \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\gamma$$\end{document}γ-irradiation of the oil. Various polar and nonpolar fragmentation products containing an isoprenoid skeleton were found to be formed via an oxidative/radiation scission of long-chain acyclic isoprenoids. Electronic supplementary material The online version of this article (doi:10.1007/s10967-016-4953-8) contains supplementary material, which is available to authorized users.

The CXCR2 antagonist AZD5069 has been synthesized in tritium and carbon-14-labelled forms. [(3) H]AZD5069 was prepared via reductive dehalogenation of an iodinated precursor with tritium gas to provide material with a specific activity of 25.1 Ci/mmol. [(14) C]AZD5069 was labelled in the pyrimidine ring from [(14) C]thiourea in an overall radiochemical yield of 18%. In addition, a synthetic route to the major metabolite of AZD5069 was developed. The synthesis of this metabolite was achieved from AZD5069 using a chemoselective Lindgren-Pinnick reaction in order to minimize oxidation of the sulphide group.

The syntheses of [(3) H]SCH 444877, [(2) H4 ]SCH 444877, and [(14) C]SCH 444877 are described. [(3) H]SCH 444877 was prepared in three steps from tritium gas. [(2) H4 ]SCH 444877 was synthesized from [(2) H4 ]ethanolamine in four steps with an overall yield of 40%. [(14) C]SCH 444877 was prepared from barium [(14) C]cyanamide in 10 steps with an overall yield of 8.1%.

The observed phenomena of changes of chemical compositions in previous reports [1, 2] allowed us to develop a phenomenological nuclear fusion-fission model with taking into consideration the elastic and inelastic scattering of photoprotons and photoneutrons, heating of surrounding deuterium nuclei, following d-d fusion reactions and fission of middle-mass nuclei by “hot” protons, deuterons and various-energy neutrons. Such chain processes could produce the necessary number of neutrons, “hot” deuterons for explanation of observed experimental results [1, 2]. The developed approach can be a basis for creation of deuterated nuclear fission reactors (DNFR) with high-density deuterium gas and the so-called deuterated metals. Also, this approach can be used for the study of nuclear reactions in high-density deuterium or tritium gas and deuterated metals.

In the interest of developing efficient methods for tritium labelling peptides, we here demonstrate the successful labelling of PACAP-38 (pituitary adenylate cyclase-activating polypeptide), a 38-mer peptide, using a synthetic diiodinated PACAP-38 precursor. In this example, we employ standard hydrogenation chemistry with the use of a heterogeneous palladium catalyst and carrier-free tritium gas on a tritium manifold system. Copyright © 2011 John Wiley & Sons, Ltd.

Metal-catalysed exchange with tritiated water and tritium gas has been extensively used to prepare a wide range of tritium-labelled compounds in support of pharmaceutical research. Examples of the utility of both heterogeneous and homogeneous metal catalysts to label a very broad range of structures will be discussed in this review. Copyright © 2010 John Wiley & Sons, Ltd.

Aqueous tritium enrichment parameters of a commercially available Iridium/Platinum (Ir/Pt) polymer electrolyte membrane (PEM) cell were determined after electrolysis of tritium aqueous standards, and compared to those of a conventional Nickel/Iron (Ni/Fe) electrochemical cell. Lower aqueous enrichment is seen in the Ir/Pt PEM electrolyzer in comparison to the conventional Ni/Fe electrolytic cell. This is explained by the values found for the PEM cell fractionation factor β Ir/Pt and electrolytic fractionation factor β eIr/Pt values determined to be 4.7 ± 0.3 (β Ni/Fe = 26), and 6.6 ± 0.7 (β eNi/Fe = 37), respectively. A direct consequence of the Ir/Pt β e value is the richer tritium gas phase produced relative to the conventional cell, which is advantageous for direct reduction of HTO to HT gas.

The combination of an Ir/Pt PEM electrolyzer with a 1 L flow-through gas proportional counter was characterized for the quantification of tritium in water. The goal of the detection system is to quantify at concentrations below the Environmental Protection Agency (EPA) primary drinking water standard (740 Bq/L) with minimal expendables. The detector operating voltage, efficiency, background count rate of the passively shielded counter were measured in order to calculate the minimum detectable concentration of the detection system. The electrolyzer fractionation factor β e value deduced from the measurement of gas phase activity concentrations generated from tritium aqueous standards was found in good agreement with literature values.

[(1R)-endo]-(+)-3-bromocamphor was dehalogenated with tritium gas to [3-3H]camphor and via [3-3H]phenylborneol converted to [3-3H]deramciclane isolated as the fumarate salt (specific activity 51.8 GBq/mmol). This three step synthesis from [3-3H]camphor gave an overall yield of 22%. Benzyloxy-acetic acid methyl ester was reduced with sodium-borotritide to 2-benzyloxy-ethanol-[1-3H], and through a four step procedure was converted to 2-dimethylaminoethyl-[2-3H] chloride. The latter was condensed with the sodium derivative of 2-phenylborneol giving rise to [2-dimethylamino-[2-3H]ethoxy]deramciclane isolated as the fumarate (specific activity 8.177 GBq/mmol). This six step synthesis from [3H]NaBH4 gave an overall yield of 6%. Copyright © 2005 John Wiley & Sons, Ltd.

A computer code named ACUTRI has been developed to assess tritium doses due to inhalation to the general public. The ACUTRI code can calculate the radiological impact of tritium gas (HT) and tritiated water (HTO) released accidentally to the atmosphere. The models in this code consist of a tritium transfer model including the oxidation of HT to HTO and the reemission of HTO from soil to the atmosphere and a dose calculation model. The atmospheric dispersion of the primary HT and HTO plumes and secondary HTO plume, which is reemitted from soil to the atmosphere, is calculated by using the Gaussian plume model. In this calculation, it is possible to analyze the meteorological data statistically, in the same way as a conventional dose assessment method according to the meteorological guideline of the Nuclear Safety Commission of Japan. Tritium concentrations in air and their resultant doses were calculated using the ACUTRI code under several conditions. In order to validate the model, calculations were compared with experimental results.

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), currently in clinical trials for the treatment of inflammatory diseases, is a potent inhibitor of p38 MAP kinase. Labeled BIRB 796 with stable and radioactive isotopes was required for metabolism, distribution, and absorption studies. We first report the synthesis of carbon-14 labeled BIRB 796 with a specific activity of 2 GBq/mmol (54.2 mCi/mmol), using [14C]-phosgene under modified Schotten–Baumann conditions; second the preparation of tritium-labeled BIRB 796 with a specific activity of 659 GBq/mmol (17.81 Ci/mmol) by reductive dehalogenation of iodo-BIRB 796 with tritium gas; and finally, the synthesis of 2H8-BIRB 796 using morpholine-2,2,3,3,5,5,6,6-2H8 with isotopic enrichment of 98.9 at% 2H. Copyright © 2004 John Wiley & Sons, Ltd.

The utility of Raman spectroscopy for noninvasive, real-time monitoring of a range of tritium gas labeling reactions has been investigated, using deuterium gas as a model in most cases. Reaction types include organoiridium-catalyzed heteroatom-directed exchange (HDE), olefin hydrogenation and catalytic aryl dehalogenation. Five examples of HDE reactions with several different substrate types were monitored by observation of Raman vibrational bands sensitive to the isotopic substitutions. Changes in peak intensities and/or frequencies associated with the course of labeling are clearly observable at concentrations and reaction scales typical of tritium gas reactions. Similarly, Raman bands sensitive to the chemical changes that occur during catalytic deuterogenation of an olefin and to catalytic deuterium–bromine exchange of an aryl bromide were successfully monitored. This methodology can provide unprecedented real-time information, otherwise difficult to obtain, over the course of such reactions. Copyright © 2004 John Wiley & Sons, Ltd.

Various approaches to the synthesis of tritium-labelled BIIL 260 with high specific radioactivity were investigated. Attempts to incorporate tritium directly into BIIL 260 were made by solid-phase isotope exchange with tritium gas and by isotope exchange with tritiated water which yielded a final product with specific activities ranging from 2 to 7 Ci/mmol. However, the solid-phase and liquid-phase dehalogenations of an appropriate synthon fragment of BIIL 260 followed by its subsequent conversion to the final product via chemical synthesis yielded the desired tritium-labelled BIIL 260 with specific activities of 25 or 71 Ci/mmol, depending upon the precursors and methods used in the dehalogenation step. Copyright © 2002 John Wiley & Sons, Ltd.

A simultaneous sampling system for the speciation of atmospheric T and 14C has been developed. Firstly tritiated moisture together with all water vapor in air is adsorbed on Drierite after coagulation using an electric cooler. Then 14CO2 plus stable CO2 in the dried air is adsorbed on molecular sieve 4A. Elemental tritium gas (HT) plus hydrogen gas (H2) in the atmosphere along with H2 gas generated from electrolysis of groundwater which does not contain any T, are oxidized on Pd catalyst to water and adsorbed on molecular sieve 3A. Tritiated methane (CH3T) and 14CH4 plus stable methane in the atmosphere are oxidized on Pt catalyst to water and CO2 under 400 °C. Then, Drierite and molecular sieve 4A adsorb the oxidized T (HTO) and C-14 (14CO2), respectively. Tritium and C-14 in surface and soil air have been measured using this system

The reaction conditions for the incorporation of tritium into zaleplon have been investigated. The methods studied were the catalytic isotope exchange reaction with tritium gas and catalytic isotope exchange reaction with tritiated water. The results showed that the latter method was the method of choice giving a compound with a higher specific activity and a better yield. Copyright © 2002 John Wiley & Sons, Ltd.

The central cannabinoid receptor antagonist SR141716, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, was synthesized from commercially available starting materials. Condensation of an aryl hydrazine with a diketone followed by base promoted isomerization/cyclization of the intermediate anti-imine gave the pyrazole acid which was converted to the title hydrazide via its acid chloride. Facile iodination via metallation followed by in situ trapping with an iodine source gave a modest yield of the iodinated SR141716. The iodine was selectively reduced with tritium gas and catalyst while retaining the three aryl chlorine atoms in the structure. The tritiated SR141716 exhibited a tritium-proton nOe both definitively identifying the position of the tritium as well as the sought isomer of the diarylpyrazole. This work provides a direct method for the preparation of preferred iodinated aryl substrates that offer advantages where selectivity and high incorporation in catalytic reduction is sought. Copyright © 2002 John Wiley & Sons, Ltd.

3H-Sch 58235 was prepared at a specific activity of 29.1 Ci/mmol by Ir(COD)(Cy3P)PyPF6 catalysed exchange with tritium gas. 14C-Sch 58235 was prepared in three steps from p-hydroxy[ring-U-14C]benzaldehyde with an overall radiochemical yield of 21%. 13C6-Sch 58235 was similarly prepared in three steps from p-hydroxy[ring-U-13C6]benzaldehyde in an overall yield of 41%. Copyright © 2002 John Wiley & Sons, Ltd.

Endomorphin-1 (EM1, Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (EM2, Tyr-Pro-Phe-Phe-NH2) are natural tetrapeptide ligands of µ-opioid receptors involved in the modulation and attenuation of pain. For a detailed examination of their receptor-binding properties and their metabolic stability, tritium-labelled EM1 and EM2 radioisotopomers were synthesized by catalytic dehalogenation or saturation of the precursor peptides with tritium gas. Amino acid analysis revealed that the tritium labelling was specific and the specifically labelled radioligands possessed high specific activity, ranging from 0.77 TBq/mmol to 2.35 TBq/mmol. The biological half-lives of the peptides in the biological matrix (295 min and 230 min for EM1 and EM2, respectively) indicate that these radioligands are appropriate for binding assays in rat brain membrane preparations. The radioisotopomers of EM2 are not statistically different in the receptor-ligand interaction, and they are excellent tools for further comparative biochemical studies. Copyright © 2001 John Wiley & Sons, Ltd.

The α,β-dehydro precursor of the delta sleep-inducing peptide (DSIP) for tritiation was prepared prior to tritiation using a 3+6 fragment coupling strategy on a solid support. The first fragment, α,β-dehydrotripeptide, was prepared in solution in five steps in 79% overall yield while the second fragment was obtained by a step by step peptide synthesis on a Wang resin using an Fmoc strategy. The α,β-dehydrotripeptide was coupled to the fragment linked to the resin, followed by a deprotection/cleavage step to yield the α,β-dehydro-DSIP, 7. Catalytic reduction of unsaturated DSIP using tritium gas and palladium oxide as catalyst gave [3H]DSIP having a specific activity of 1.184 TBq/mmol(32 Ci/mmol). Copyright © 2001 John Wiley & Sons, Ltd.

Catalytic dehalogenation of 2-chloroadenosine with tritium gas led to tritium labelled adenosine which was subsequently alkylated with (E)-4-t-butoxy-3-methylbut-2-enyl bromide or with 3-methylbut-2-enyl bromide to yield labelled (E)-N6-(4-t-butoxy-3-methylbut-2-enyl)adenosine (2a) and N6-(3-methylbut-2-enyl)adenosine (2b). Acidic hydrolysis of 2b gave N6-(3-methylbut-2-enyl)adenine while acidolysis of 2a with trifluoroacetic acid led to a mixture of (E)-zeatin riboside and (E)-zeatin. Hydrogenation of (Z/E)-zeatin riboside (3H2, PdO/BaSO4) afforded labelled dihydrozeatin riboside and, after hydrolysis, dihydrozeatin. Copyright © 2000 John Wiley & Sons, Ltd.

The synthesis of tritium and carbon-14 labeled robalzotan is described. Tritiated robalzotan 8 was obtained after catalytic hydrogenation of (R)-methyl 6-bromo-3-(N,N-dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxylate (7) with tritium gas using palladium as a catalyst. The corresponding carbon-14 labeled compound 11 was obtained by cyanylation of (R)-3-N,N-dicyclobutylamino-8-fluoro-5-trifluoromethane-sulfonyloxy-3,4-2H-1-benzopyran. The nitrile was subsequently hydrolyzed and converted to carbon-14 labeled robalzotan. Copyright © 2000 John Wiley & Sons, Ltd.

A number of physiologically active compounds—steroid hormones, some phytohormones, carbohydrates and nicotinamide adenine dinucleotide—have been tritiated using high specific activity tritiated water produced by the oxidation of tritium gas on palladium oxide and in the presence of a dry organic solvent. In the process the effect of various variables such as catalyst and solvent have been investigated. The products so obtained had specific activities in the range 3–25 Ci/mmol. Copyright © 1999 John Wiley & Sons, Ltd.

Key step of the synthesis of calcium antagonist MN-9201 was the cyclizing addition of the allyl-3-amino-crotonate onto methyl 2-[(3-nitrophenyl) methylene]-3-oxobutanoate. It was then used to synthesize [Allyl-2,3-3H]-MN-9201 by the catalytic addition of tritium gas. Its radiochemical purity and specific activity were 98% and 2.1 TBq/mmol, respectively. © 1998 John Wiley & Sons, Ltd.

[ 3 H]-Cyclosporin A labeled at the first amino acid ([ω- 3 H-MeBmt 1 ]CS) has been prepared by tritium gas hydrogenolysis of [O-acetyl-ω-bromo-MeBmt 1 ]CS followed by deprotection with methanolic sodium methoxide. The requisite bromo intermediate was prepared by bromination of [O-acetyl-MeBmt 1 ]CS with N-bromosuccinimide. After synthesis and purification, 2.45 mg of [ω 3 H-MeBmt 1 ]CS with a total activity of 327 MBq were produced with a radiochemical purity >97 %, and specific activity of 160 GBq/mmol (4.3 Ci/mmol).

Synthesis of [2,3- 3 H]-n-butyl alcohol consisted of two steps: crotonaldehyde was reduced with lithium aluminum hydride to crotyl alcohol, which with the catalytic addition of tritium gas was transformed to [2,3- 3 H]-n-butyl alcohol. Its specific activity and radiochemical purity were 29 TBq/g and 99%, respectively.

The tritium exchange labeling of a variety of complex compounds is achieved in the presence of catalyst precursor [(cod)Ir(PPh 3 ) 1 ]BF 4 and limited amounts of tritium gas. The regioselectivity of exchange is high and consistent with empirical rules previously observed. High specific activity levels are often achieved, usually with specific aryl C-H bonds. However, remarkably efficient exchange occurs in certain N-alkyl groups. Studies of intermolecular inhibition of catalytic exchange suggest reasons why larger amounts of complex are sometimes required to label complex molecules; nevertheless, significant amounts of label incorporation into substrates can be achieved even starting with small amounts of labeling gas.

( 3 H)-Azoxybacilin, a new antifungal agent, was prepared in five steps. The label was introduced by reduction of 2-t-butoxycarbonylamino-succinic-acid-1-t-butylester-carbonic-acid-ethylester anhydride (2) with LiB 3 H 4 generated from tritium gas via Li 3 H.

Simple and facile syntheses of highly deuterated and tritiated LiBH 4 , NaBH 4 and KBH 4 were achieved by hydrogen isotope exchange with deuterium or tritium gas at elevated temperatures. The exchange products were characterized by boron, proton and deuterium or tritium NMR spectroscopy. The extent of isotope ( 2 H or 3 H) incorporation was calculated from the patterns of 11 B NMR spectra. Several samples of tritiated NaBH 4 were treated with BF 3 -Et 2 O to produce tritiated borane-THF complex, which is an electrophilic reducing agent. The utility of both the borohydride reagents and borane-THF complex in labelling reactions was confirmed by exemplary reductions leading to specifically labelled products. The extent and orientation of labelling in the reduction products was assessed by a combination of radio-HPLC analysis, 1 H, 2 H or 3 H NMR and mass spectrometry.

The tritium labeled form of 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine ( 3 H-SCH 58261) was obtained by reduction of 5-amino-7-[2-(2',4',5'-tribromo)-phenylethyl]-2-(2-furyl)-pyrazolo[4,3-e] 1,2,4-triazolo[1,5-c]pyrimidine with tritium gas in the presence of 10% Pd-C. Final product was purified by HPLC to give the title 3 H-SCH 58261 with radiochemical purity of 99% and specific activity of 68.6 Ci/mmol. 3 H-SCH 58261 bound A 2A receptors in rat striatal membranes (specific binding > 90%) with Kd and Bmax value of 0.70 nM and 971 fmol/mg of protein, respectively. 3 H-SCH 58261 represents a useful tool for a further characterization of A 2A adenosine receptor subtype

A procedure for high level tritium labelling at the C2-H position of adenosine 5'-triphosphate ([2- 3 H]-ATP, 1), based on the tritiodehalogenation reaction of 2-bromoadenosine 5'-triphosphate (2) has been elaborated. This precursor was prepared in a six-step synthesis from guanosine. The tritiodehalogenation of (2) for three hours over palladium oxide in phosphate buffer yielded tritium labelled ATP with high specific activity, in good chemical yield.

At room-temperature and atmospheric pressure, using electrode disks of various sizes, under the action 4 ∼ 7Vdc eletric field, we gettered tritium gas from 2.2L of air containing (0.15 ∼ 18.61)×108 Bq of tritium and (3000 ∼ 12000) ppm of moisture during 50 hours or so the efficiency of gettering tritium was over 95%. Applying liquid scintillation counting method, we measured the tritium in the disks after gettering, and found that the amounts of tritium in the disks were equal to those reduced in the tested tritiated air.

A procedure for the preparation of methyl iodide- 3 H 3 of high specific activity starting with tritium gas, its use for the synthesis of tritium-labeled L-methionine-[methyl- 3 H 3 ] are described. The tritiated L-methionine can be used as a building block for the preparation of tritium labeled peptide containing terminal L-methionine

We describe herein the synthesis of polybromodiphenylacetic acid (4), a fragment common to the tritiation substrates (8) and (11) of the sodium channel blocker, PD-85639 (1) and the angiotensin II inhibitor EXP-655 (2) respectively. Preparation of (8) and (11) followed by reductive debromonation with carrier free tritium gas furnished the corresponding receptor ligands (1) and (2) having specific activities of 180 Ci/mmole and 209 Ci/mmole, respectively

A tritium labelled antihistamine, N,N-diethyl-2-[4-(phenyl-methyl)phenoxy]-ethaneamine. HCl (DPPE, 4) was synthesized to investigate its binding characteristics to intracellular histamine receptors (H IC ) and for further studies with specific ligands of H IC to determine their potential effects on cell proliferation. A palladium catalyzed reduction of an activated carbonyl between the two phenyl groups of N,N-diethyl-2-[4-(benzoyl)phenoxy]-ethaneamine. HCl (DBPE, 3) with 100% tritium gas was successful, where 55% of the theoretical activity (specific activity 31.6 Ci/mmol) was obtained.

The experimental conditions which control the exchange from deuterium or tritium gas into the C-1 proton position of glucose in aqueous solution have been studied in detail, with a view to determining the factors which maximize exchange into glucose, but minimize exchange into the solvent water. The favoured conditions for producing glucose with close to 100% isotope labelling in the C-1 position, and with negligible formation of labelled byproducts, were a reaction time of 6 to 8 hours, a temperature of 60°C, and a pH of 7 or higher. Pd/BaSO 4 was the preferred catalyst and slow pre-addition of the deuterium or tritium gas to the catalyst bed was essential to maximize the subsequent isotope exchange into the substrate.

One of the radiological problems encountered in tritium handling facilities is the hazards associated with tritium's ability to label and degrade organic materials. Experiments in which male hairless rats have been contaminated with tritium-gas-contaminated pump oil have demonstrated that tritium deposited on the skin provides an input of organically bound tritium and tritiated water in the body. The accumulation of organically bound tritium at the point of contact in the skin and in various tissues influenced tritium excretion in urine and feces. The retention of tritium in the body showed that tritium was mainly metabolized and assimilated as organically bound tritium. The distribution of tritiated water was rapid and uniform in the whole-body. Analyses of tritium excreted in animal urine and feces showed that a significant level of organically bound tritium was excreted shortly after exposure. The highest concentration of tritium activity was measured in the exposed area of the skin. An increased level of tritium accumulation in the liver and kidneys was seen. Dose calculations showed that the exposed skin had the highest dose, and the skin dose was primarily due to the retention of organically bound tritium at the point of contact. The interpretation of these data has indicated that the retention of short-term organically bound tritium in the skin may be a dominant factor for dosimetry purposes.

A selective total synthesis of [11,12- 3 H]-9-cis-retinoic acid 1 at a specific activity of 46 Ci/mmole is described. The alkyne 4, efficiently prepared in two steps from readily available starting materials, was partially reduced to 9,11-di-cis-retinoic acid 3 with both deuterium and tritium gas. Selective isomerization of 3 to 1 is discussed, as well as non-selective direct conversions of 4 to 1

We have synthesized two tritium labelled photolabile azid-α-desmethylbenzphetamine analogues: N-benzyl-N-methyl-p-azido-phenethylamine ([3H]BP-N3) and N-(p-azidobenzyl)-N-methyl-p-azido-phenethylamine ([3H]N3-BP-N3). These compounds, photoaffinity probes for cytochrome P450 2B1, were prepared in a two step synthetic process. First, the iodinated aminoderivative precursors N-benzyl-N-methyl-4-amino-3,5-diiodophenethylamine and N-(4-amino-3,5-diiodobenzyl)-N-methyl-4-amino-3,5-diiodophenethylamine were subjected to reductive deiodination on a Pd/C catalyst using sodium [3H]borohydride as an in situ generator of tritium gas. Second, resultant radiolabelled amino-compounds were converted into the final [3H]BP-N3 and [3H]N3-BP-N3 compound through their diazoderivatives without separation of their intermediates.

A range of organic substrates was successfully exchanged with tritium gas using NaBH4-reduced palladium oxide or chloride as catalyst. Exchange conditions involved a reaction temperature of 100 °C, a reaction time of 3 days, and products were analyzed by radio-gas chromatography and 3H NMR spectroscopy. Both aromatic and aliphatic compounds underwent exchange, 18 of the 22 substrates incorporated > 35% of the available tritium, and most products showed high radiochemical purity. 3H NMR analyses showed that both alkanes and the alkyl chains of alkylbenzenes were rapidly and evenly labelled. Some aromatic compounds showed general ring exchange while others showed high specificity. These results for bulk palladium catalyst are strikingly different from those obtained with bulk platinum and supported palladium catalysts. The results are discussed in terms of currently accepted mechanisms of heterogeneous metal catalyzed hydrogen isotope exchange reactions.

The enantiomers of [3-3H]-2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]ethanol,[3-3H]-hydroxychloroquine, (R)-8 and (S)-8, have been prepared in two steps from the known precursors 4,7-dichloro-3-iodoquinoline, 4, and the enantiomers of 2-[(4-aminopentyl)ethylamino]ethanol, (R)-2 and (S)-2, by formation of the enantiomers of 2-[[4-[(7-chloro-3-iodo-4-quinolinyl)amino]pentyl]ethylamino]ethanol, (R)-3 and (S)-3, and subsequent reductive deiodination with tritium gas over 10% palladium on charcoal.

In the search for a radioactive form of the peptidomimetic renin inhibitor, ditekiren, with a metabolically suitable radiolabel for conducting drug disposition studies, we prepared [3H]ditekiren with tritium labels in the N-methyl-histidine moiety and in the leu-val alcohol transition-state insert. [His-3H]ditekiren was obtained by first introducing two iodine substituents into the N-methyl-histidine moiety of the parent drug, followed by catalytic hydrodehalogenation with tritium gas. Administration of this labeled drug to monkeys, however, resulted in prolonged retention of radioactivity in the test animals, even though little or no tritiated water was detected in urine. This suggested in vivo production of a labeled fragment from the drug, e.g., N-methyl-[3H]histidine, which became incorporated into the endogenous amino acid pool. These results, together with similar earlier findings after administration of [3H]ditekiren labeled in the proline moiety of the drug, led us to synthesize [3H]ditekiren labeled in the “unnatural” leu-val alcohol (LVA) portion of the molecule. [LVA-3H]ditekiren was obtained by first oxidizing the parent drug to produce an LVA-keto analog, which was then reduced with sodium borotritide to give a mixture of tritium labeled ditekiren and its LVA-epimer. The two epimeric labeled materials were separated and purified by means of preparative high performance liquid chromatography (HPLC). The tritium label in [LVA-3H]ditekiren was found to be metabolically suitable for conducting drug disposition studies, with no liability for tritiated water production or prolonged retention of radioactivity in tissues of test animals.

2-Octyl-4H-1,3,2-benzodioxaphosphorin 2-oxide (octyl-BDPO) was labelled with tritium in the 7,8-octyl and 6-BDPO positions at specific activities of 38 and 16 Ci/mmol, respectively, by catalytic reductions of the corresponding olefin and bromo precursors with tritium gas. This potent mechanism-based inhibitor for neuropathy target esterase (NTE) (I50 = 0.25 nM) and delayed neurotoxicant (active in hens at 3 mg/kg) was designed to determine phosphorylated NTE which retains the octyl label and differentiate aging with or without intramolecular group transfer (“alkylation”) reactions at the NTE active site from the fate of the aryl label.

The hydrogen isotope exchange of Brefeldin-A with tritium gas (T2) in 1,4-dioxane was studied over a commercial palladium catalyst supported on diatomaceous earth (5% metallic weight). The effect of the gas phase was studied. Addition of air in the gas phase led to an increase of the catalytic activity. Moreover, exchange was enhanced when the air/T2 ratio reached a value of 4. This latter result is interpreted, principally, in terms of a strongly poisoning of the metallic particles together with an effect of the T2 partial pressure. Through the comparison with Pd(II) oxide, the role of the support is also shown. The specific activities ranged up to 2.8 Ci/mMoles. The labelled product was analyzed by 3H NMR. Possible mechanisms for tritium incorporation are discussed and two different adsorbed species, on the catalyst surface, are involved.

In micro-scale experiments, [2-14C,5-3H]cytosine and [2-14C,5-3H] uracil were synthesized via bromination and catalytic Br-3H exchange reaction with the use of [2-14C]-cytosine and-uracil and tritium gas. The double labelling percentages of these products were 70 and 26, respectively. It was assumed that [2-14C,5-Br] uracil was subjected to reaction with hydrogen atom originally adsorbed on a palladium catalyst. This is to a lesser extent valid for [2-14C,5-Br]cytosine. The percentages of 3H labelling at 5 position of pyrimidine ring of cytosine and uracil were proved to be 96 and 73, respectively. For the analysis and purification of products, the HPLC eluting conditions using C18 reverse column and NaH2PO4 aqueous solution or H2O/methanol mixture as eluent were studied. Unreacted tritium gas was recovered with the use of adsorbents such as active charcoal and Zr-V-Fe getter.

Tritium labelled FPL 64176 (1, methyl 2,5-dimethyl-4-2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate), a potent calcium channel activator with insulinotropic properties was synthesized from the corresponding bromo derivative (3) using tritium gas and Pd/C catalyst. (3) was in turn prepared from methyl 2,5-dimethylpyrrole-3-carboxylate (4) in a one pot procedure. The specific activity of [3H]FPL 64176 was 38 mCi/mmol and radiochemical purity >98%.

Platinum-loaded microporous aluminophosphate molecular sieves (Pt-AlPO4-5) were synthesized and studied as catalysts for promoting tritium isotope labelling by exchange between tritium gas and aromatic, heteroaromatic and aliphatic hydrocarbons. The presence of the Pt metal considerably enhanced the activation of the tritium gas. Detailed isotope orientation patterns, as determined by 3H nmr spectroscopy, showed that the AlPO4-5 component of the catalyst dominated the exchange reactions, but some influence of the Pt metal was apparent with some substrates.

Age dependence of tritium gas (HT) oxidation in rats was investigated in in vitro experiments using faecal suspensions and intestinal contents from rats. HT oxidation was determined as the fixation of HT in faeces or intestinal contents suspended with GAM medium at 30°C under anaerobic and aerobic conditions. The HT oxidation rate in faecal suspension under anaerobic conditions was almost constant irrespective of age and about 10 times that under aerobic conditions in 10 to 100 week old rats. The viable cell number of anaerobic microbes in faeces was 3-4 times that of aerobic microbes (facultative anaerobes) and tended to decrease with age in each case