Dataset Information

Rapid and Efficient Synthesis of [11C]Trifluoromethylarenes from Primary Aromatic Amines and [11C]CuCF3.

ABSTRACT: Prior studies have shown that trifluoromethylarenes can be labeled in high molar activities (A m > 200 GBq/?mol) with positron-emitting carbon-11 (t 1/2 = 20.4 min) by the reaction of the copper(I) derivative of [11C]fluoroform [11C]CuCF3, with several types of precursors, such as aryl iodides, arylboronic acids, and aryldiazonium salts. Nonetheless, these precursors can be challenging to synthesize, and in the case of diazonium salts, are unstable. Methods that reduce challenges in precursor preparation for the synthesis of [11C]trifluoromethylarenes are desirable to enhance possibilities for developing biologically relevant 11C-labeled compounds as radiotracers for biomedical imaging with positron emission tomography (PET). Here, we explored the production of no-carrier-added [11C]trifluoromethylarenes from commercially available primary aromatic amines through reactions of [11C]CuCF3 with diazonium salts that were generated in situ. Moderate to high isolated decay-corrected radiochemical yields (RCY) (32-84%) were obtained rapidly (within 2 min) for many para-substituted and meta-substituted primary aromatic amines bearing a halo, methoxy, thiomethyl, hydroxy, nitro, nitrile, carboxyl, ethylcarboxy, or trifluoromethyl substituent. Null to low RCYs (0-13%) were observed only for ortho bromo-, nitro-, or nitrile-substituted precursors. This new radiosynthetic method usefully expands options for producing PET radiotracers bearing a [11C]trifluoromethyl group, especially from aryl amine precursors.

SUBMITTER: Young NJ

PROVIDER: S-EPMC7424730 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Rapid and Efficient Synthesis of [11C]Trifluoromethylarenes from Primary Aromatic Amines and [11C]CuCF3.

Young Nicholas J NJ Pike Victor W VW Taddei Carlotta C

ACS omega 20200728 31

Prior studies have shown that trifluoromethylarenes can be labeled in high molar activities (A m > 200 GBq/μmol) with positron-emitting carbon-11 (t 1/2 = 20.4 min) by the reaction of the copper(I) derivative of [11C]fluoroform [11C]CuCF3, with several types of precursors, such as aryl iodides, arylboronic acids, and aryldiazonium salts. Nonetheless, these precursors can be challenging to synthesize, and in the case of diazoniu ...[more]

PMID: 32803050

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Project description:Arylamines (AAs) and heterocyclic aromatic amines (HAAs) are structurally related carcinogens formed during the combustion of tobacco or cooking of meat. They undergo cytochrome P450 mediated N-hydroxylation to form metabolites which bind to DNA and lead to mutations. The N-hydroxylated metabolites of many AAs also can undergo a co-oxidation reaction with oxy-hemolgobin (HbO2) to form methemoglobin (met-Hb) and the arylnitroso intermediates, which react with the ?-Cys(93) chain of Hb to form Hb-arylsulfinamide adducts. The biochemistry of arylamine metabolism has been exploited to biomonitor certain AAs through their Hb arylsulfinamide adducts in humans. We examined the reactivity of HbO2 with the N-hydroxylated metabolites of 4-aminobiphenyl (ABP, HONH-ABP), aniline (ANL, HONH-ANL), and the HAAs 2-amino-9H-pyrido[2,3-b]indole (A?C, HONH-A?C), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP, HONH-PhIP), and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx, HONH-MeIQx). HONH-ABP, HO-ANL, and HONH-A?C induced methemoglobinemia and formed Hb sulfinamide adducts. However, HONH-MeIQx and HONH-PhIP did not react with the oxy-heme complex, and met-Hb formation and chemical modification of the ?-Cys(93) residue were negligible. Molecular modeling studies showed that the distances between the H-ON-AA or H-ON-HAA substrates and the oxy-heme complex of HbO2 were too far away to induce methemoglobinemia. Different conformational changes in flexible helical and loop regions around the heme pocket induced by the H-ON-AA or H-ON-HAAs may explain the different proclivities of these chemicals to induce methemoglobinemia. Hb-Cys(93?) sulfinamide and sulfonamide adducts of ABP, ANL, and A?C were identified, by Orbitrap MS, following the proteolysis of Hb with trypsin, Glu-C, or Lys-C. Hb sulfinamide and sulfonamide adducts of ABP were identified in the blood of mice exposed to ABP, by Orbitrap MS. This is the first report of the identification of intact Hb sulfinamide adducts of carcinogenic AAs in vivo. The high reactivity of HONH-A?C with HbO2 suggests that the Hb sulfinamide adduct of A?C may be a promising biomarker of exposure to this HAA in humans.

Dataset Information

Rapid and Efficient Synthesis of [11C]Trifluoromethylarenes from Primary Aromatic Amines and [11C]CuCF3.

Publications

Rapid and Efficient Synthesis of [<sup>11</sup>C]Trifluoromethylarenes from Primary Aromatic Amines and [<sup>11</sup>C]CuCF<sub>3</sub>.

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