[14C]Dimethyltitanocene and [14C]Methyl(methyltrimethylsilyl) titanocene–Reagents for the [14C]olefination of carbonyl compounds: synthesis of [14C]Aprepitant

A neurokinin (NK‐1) receptor antagonist, [¹⁴C]Aprepitant, was synthesized using two labeled olefination reagents: [¹⁴C]dimethyltitanocene 1 and [¹⁴C]methyl (methyltrimethylsilyl)titanocene 7. Both reagents can be readily prepared from [¹⁴C]methyllithium and have been shown to convert a variety of carbonyls to [¹⁴C]methylenes in good radiochemical yields. Copyright © 2009 John Wiley & Sons, Ltd.     

Untersuchungen mit C14-markierten Digitalis-Stoffen

Ohne Zusammenfassung     

Uptake and distribution of 14C during and following exposure to [14C]methyl isocyanate

Guinea pigs were exposed to [14C]methyl isocyanate (14CH3-NCO, 14C MIC) for periods of 1 to 6 hr at concentrations of 0.5 to 15 ppm. Arterial blood samples taken during exposure revealed immediate and rapid uptake of 14C. Clearance of 14C was then gradual over a period of 3 days. Similarly 14C was present in urine and bile immediately following exposure, and clearance paralleled that observed in blood. Guinea pigs fitted with a tracheal cannula and exposed while under anesthesia showed a reduced 14C uptake in blood indicating that most of the 14C MIC uptake in normal guinea pigs occurred from retention of this agent in the upper respiratory tract passages. In exposed guinea pigs 14C was distributed to all examined tissues. In pregnant female mice similarly exposed to 14C MIC, 14C was observed in all tissues examined following exposure including the uterus, placenta, and fetus. While the form of 14C distributed in blood and tissues has not yet been identified, these findings may help to explain the toxicity of MIC or MIC reaction products on organs other than the respiratory tract, as noted by several investigators.     

Demonstration of 3,4-dihydroxy(14C)benzoic acid and (14C)vanillic acid after administration of (14C)noradrenaline in the rat

Rats were injected with 40 μCi (±)-[1-³H]noradrenaline and 10 μCi ±-[1-¹⁴C]noradrenaline. Three fractions with a decreased ³H:¹⁴C ratio were isolated from the urine by a combined alumina adsorption-ethyl acetate extraction procedure. Two of the fractions were identified as [¹⁴C]vanillic acid and 3,4-dihydroxy[¹⁴C]benzoic acid, respectively. Vanillic acid represented between 1.5 and 3.0% of the total [¹⁴C]activity excreted within 24 h and the contribution of dihydroxybenzoic acid was 0·2-0·5%. The third fraction with a decreased ³H: ¹⁴C ratio has not been identified and represented about 2% of the total [¹⁴C]activity excreted within 24 h. After monoamine oxidase blockade with 100 mg/kg of iproniazid, the excretion of vanillic acid, 3,4-dihydroxybenzoic acid and the unknown fraction was greatly diminished. The probability that these three substances represent those metabolites arising simultaneously with the formation of tritium water from (±)-[1-³H]noradrenaline is discussed.     

Excretion and distribution of [14C]rhein and [14C]rhein anthrone in rat

After single intracaecal administration of [14C]rhein (25 mg kg-1) and [14C]rhein anthrone (20 mg kg-1) to rats, the summated recovery rates of 14C after five days were in urine 37(+/- 8.3)% and 2.8(+/- 0.4)% and in faeces 53(+/- 9.5)% and 95 (+/- 10.1)%, respectively. The clearance of radioactivity from the organs and tissues was almost complete within three days, with the exception of the kidney which exhibited pronounced retention of radioactivity even after five days (less than 61% of 24 h values). Extracts of faeces from animals treated with [14C]rhein of [14C]rhein anthrone, revealed rhein as well as other radioactive substances, which chemically did not react as 1,8-dihydroxyanthraquinones.     

Synthesis of [14C] Sarin

Synthetic routes for the synthesis of [¹⁴C] sarin and related nerve agents are described. Triethyl phosphite and [¹⁴C] methyl iodide are reacted in the Michaelis–Arbusov reaction to produce diethyl methyl phosphonate which is converted to methylphosphonic acid by hydrolysis. After chlorination and subsequent fluorination the final product is formed by reaction with the appropriate alcohol. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of [14C]omarigliptin

An efficient synthesis for [¹⁴C]Omarigliptin (MK‐3102) is described. The initial synthesis of a key ¹⁴C‐pyrazole moiety did not work due to the lack of stability of ¹⁴C‐DMF‐DMA reagent. Thus, a new radiolabeled synthon, ¹⁴C‐biphenylmethylformate, was synthesized from ¹⁴C‐sodium formate in one step in 92% yield and successfully used in construction of the key ¹⁴C‐pyrazole moiety. Regioselective N‐sulfonation of the pyrazole moiety was achieved through a dehydration‐sulfonation‐isomerization sequence. [¹⁴C]MK 3102 was synthesized in five steps from ¹⁴C‐biphenylmethylformate with 25% overall yield.     

Cholestyramine-Enhanced Fecal Elimination of Carbon-14 in Rats after Administration of Ammonium [14C]Perfluorooctanoate or Potassium [14C]Perfluorooctanesulfonate

Cholestyramine-Enhanced Fecal Elimination of Carbon-14 in Ratsafter Administration of Ammonium [¹⁴C]Perfluorooctanoate orPotassium [^l4C]Perfluorooctanesulfonate. JOHNSON, J. D., GIBSON,S. J., AND OBER, R. E. (1984). Fundam. Appl. Toxicol. 4, 972–976.After a single intravenous dose of ammonium [^l4C]perfluorooctanoate([¹⁴C]PFO, 13.3 mg/kg) or of potassium [¹⁴C]perfluorocctanesulfonate([¹⁴C]PFOS, 3.4 mg/kg) to rats, cholestyramine fed daily asa 4% mixture in feed was shown to increase the total carbon-14eliminated via feces and to decrease liver concentration ofcarbon-14. Rats were fed cholestyramine in feed for 14 daysafter administration of [¹⁴C]PFO and for 21 days after administrationof [¹⁴C]PFOS. Control rats were administered radiolabeled fluorochemicalbut were not treated with cholestyramine. Cholestyramine treatmentincreased mean cumulative carbon-14 elimination in feces by9.8-fold for rats administered [¹⁴C]PFO and by 9.5-fold forrats administered [¹⁴C]PFOS. After [¹⁴C]PFO, a mean of 4% ofthe dose of carbon-14 was in liver of cholcstyramine-trcatedrats at 14 days versus 7.6% in control rats; after [¹⁴C]PFOS,11.3% of the dose was in liver at 21 days versus 40.3% in controlrats. After administration of either radiolabeled compound,plasma and red blood cell carbon-14 concentrations, which wererelatively lower than liver concentrations, were also significantlyreduced by cholestyramine treatment.