Facile and Efficient Postsynthetic Tritium Labeling Method Catalyzed by Pd/C in HTO

Maegawa, Tomohiro; Hirota, Kosaku; Tatematsu, Kenjiro; Mori, Yoshihide; Sajiki, Hironao

doi:10.1021/jo0517545

Cited by 15 publications

(8 citation statements)

References 15 publications

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“…3 H-CLR01 was prepared by Moravek Biochemicals (Brea, CA) using a method that provides 3 H incorporation into the hydrocarbon skeleton (i.e., non-labile protons) [20] yielding pure 3 H-CLR01 with specific activity 1.3 Ci/mmol.…”

Section: Methodsmentioning

confidence: 99%

Safety and pharmacological characterization of the molecular tweezer CLR01 – a broad-spectrum inhibitor of amyloid proteins’ toxicity

Attar

Chan

Klärner

et al. 2014

BMC Pharmacol Toxicol

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BackgroundThe “molecular tweezer” CLR01 is a broad-spectrum inhibitor of abnormal protein self-assembly, which acts by binding selectively to Lys residues. CLR01 has been tested in several in vitro and in vivo models of amyloidoses all without signs of toxicity. With the goal of developing CLR01 as a therapeutic drug for Alzheimer’s disease and other amyloidoses, here we studied its safety and pharmacokinetics.MethodsToxicity studies were performed in 2-m old wild-type mice. Toxicity was evaluated by serum chemical analysis, histopathology analysis, and qualitative behavioral analysis. Brain penetration studies were performed using radiolabeled CLR01 in both wild-type mice and a transgenic mouse model of Alzheimer’s disease at 2-m, 12-m, and 22-m of age. Brain levels were measured from 0.5 - 72 h post administration.ResultsExamination of CLR01’s effect on tubulin polymerization, representing normal protein assembly, showed disruption of the process only when 55-fold excess CLR01 was used, supporting the compound’s putative “process-specific” mechanism of action.A single-injection of 100 mg/kg CLR01 in mice – 2,500-fold higher than the efficacious dose reported previously, induced temporary distress and liver injury, but no mortality. Daily injection of doses up to 10 mg/kg did not produce any signs of toxicity, suggesting a high safety margin.The brain penetration of CLR01 was found to be 1 - 3% of blood levels depending on age. Though CLR01 was almost completely removed from the blood by 8 h, unexpectedly, brain levels of CLR01 remained steady over 72 h.ConclusionEstimation of brain levels compared to amyloid β-protein concentrations reported previously suggest that the stoichiometry obtained in vitro and in vivo is similar, supporting the mechanism of action of CLR01.The favorable safety margin of CLR01, together with efficacy shown in multiple animal models, support further development of CLR01 as a disease-modifying agent for amyloidoses.

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Section: Methodsmentioning

confidence: 99%

Safety and pharmacological characterization of the molecular tweezer CLR01 – a broad-spectrum inhibitor of amyloid proteins’ toxicity

Attar

Chan

Klärner

et al. 2014

BMC Pharmacol Toxicol

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“…The use of (1,5-cyclooctadiene)Ir(pentane-2,4-dionate) under similar reaction conditions has been reported 174 to lead to deuterium exchange into the b-positions of some a,b-unsaturated carbonyl systems (e.g., [88][89][90]. The use of (1,5-cyclooctadiene)Ir(pentane-2,4-dionate) under similar reaction conditions has been reported 174 to lead to deuterium exchange into the b-positions of some a,b-unsaturated carbonyl systems (e.g., [88][89][90].…”

Section: Exchange Catalyzed By Iridium Dionatesmentioning

confidence: 87%

“…The 'catalytic' hydrogen gas rapidly becomes equilibrated with solvent deuterium 104 . Very dilute tritiated water was used as proof of principle 105 , but this method would not be practical in its current form for the preparation of high specific activity compounds because it requires neat water as solvent/labeling source.…”

Section: Palladiummentioning

confidence: 99%

Preparation of Tritium‐Labeled Compounds by Isotope Exchange Reactions

Voges¹,

Heys

Moenius

2009

Preparation of Compounds Labeled With Tritium and Carbon‐14

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“…The synthesis of 3 H‐dehydroabietinol was conducted using slight modifications to a previously reported method for 1 H‐ 3 H exchange of benzylic hydrogens . Briefly, dehyroabietinol (1 mmol, 286 mg) was dissolved in 2 mL of a 50:50 mixture of 3 H 2 O (5 Ci/mL, American Radiolabeled Chemicals, Inc.) and THF containing Pd/C (29 mg, 3% Pd on activated carbon, Acros Organics) in a 50 mL round bottom flask.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of the efficiency of Pd/H₂‐catalyzed benzylic H/D exchange of dehydroabietinal with D₂O and synthesis of a tritium‐labeled analogue

Petros

Shah

2013

Labelled Comp Radiopharmac

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Dehydroabietinal (DA) has been identified as an important signaling molecule in systemic acquired resistance in plants. Deuterium and tritium-labeled DA were synthesized to confirm its role in signaling and to further elucidate the mechanism by which DA induces systemic acquired resistance. Pd/H2 -catalyzed exchange of benzylic hydrogen atoms of DA with (2) H-H2 O or (3) H-H2 O was conducted with >97% label incorporation for (2) H-DA and a specific activity of 12.6 mCi/mmol for (3) H-DA synthesized from 90 mCi/mmol (3) H-H2 O. The extent of deuterium labeling at each benzylic position was determined via an inverse-gated (13) C NMR experiment. C7 and C15 were 87% and 81% labeled, respectively. Isotope-induced chemical shift changes at C6 were used to approximate the amount of singly (66%) and doubly (17%) labeled (2) H-DA at C7. Results also indicated that two of the three benzylic protons in DA underwent facile exchange. Exchange at the remaining position was likely hampered by steric interactions of nearby methyl groups at the surface of the Pd catalyst.

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Facile and Efficient Postsynthetic Tritium Labeling Method Catalyzed by Pd/C in HTO

Cited by 15 publications

References 15 publications

Safety and pharmacological characterization of the molecular tweezer CLR01 – a broad-spectrum inhibitor of amyloid proteins’ toxicity

Safety and pharmacological characterization of the molecular tweezer CLR01 – a broad-spectrum inhibitor of amyloid proteins’ toxicity

Preparation of Tritium‐Labeled Compounds by Isotope Exchange Reactions

Evaluation of the efficiency of Pd/H₂‐catalyzed benzylic H/D exchange of dehydroabietinal with D₂O and synthesis of a tritium‐labeled analogue

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Facile and Efficient Postsynthetic Tritium Labeling Method Catalyzed by Pd/C in HTO

Cited by 15 publications

References 15 publications

Safety and pharmacological characterization of the molecular tweezer CLR01 – a broad-spectrum inhibitor of amyloid proteins’ toxicity

Safety and pharmacological characterization of the molecular tweezer CLR01 – a broad-spectrum inhibitor of amyloid proteins’ toxicity

Preparation of Tritium‐Labeled Compounds by Isotope Exchange Reactions

Evaluation of the efficiency of Pd/H2‐catalyzed benzylic H/D exchange of dehydroabietinal with D2O and synthesis of a tritium‐labeled analogue

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Evaluation of the efficiency of Pd/H₂‐catalyzed benzylic H/D exchange of dehydroabietinal with D₂O and synthesis of a tritium‐labeled analogue