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Abstract
BackgroundFormamides are common motifs of biologically-active compounds (e.g. formylated peptides) and are frequently employed as intermediates to yield a number of other functional groups. A rapid, simple and reliable route to [carbonyl-11C]formamides would enable access to this important class of compounds as in vivo PET imaging agents.ResultsA novel radiolabelling strategy for the synthesis of carbon-11 radiolabelled formamides ([11C]formamides) is presented. The reaction proceeded with the conversion of a primary amine to the corresponding [11C]isocyanate using cyclotron-produced [11C]CO2, a phosphazene base (2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine, BEMP) and phosphoryl chloride (POCl3). The [11C]isocyanate was subsequently reduced to [11C]formamide using sodium borohydride (NaBH4). [11C]Benzyl formamide was obtained with a radiochemical yield (RCY) of 80% in 15 min from end of cyclotron target bombardment and with an activity yield of 12%. This novel method was applied to the radiolabeling of aromatic and aliphatic formamides and the chemotactic amino acid [11C]formyl methionine (RCY = 48%).ConclusionsThis study demonstrates the feasibility of 11C-formylation of primary amines with the primary synthon [11C]CO2. The reactivity is proportional to the nucleophilicity of the precursor amine. This novel method can be used for the production of biomolecules containing a radiolabelled formyl group.
Highlights
IntroductionFormamides are common motifs of biologically-active compounds (e.g. formylated peptides) and are frequently employed as intermediates to yield a number of other functional groups
Formamides are common motifs of biologically-active compounds and are frequently employed as intermediates to yield a number of other functional groups
By combining benzylamine (4.7 μmol, 1 equiv.), BEMP (3.7 equiv.), [Carbon-11 labelled carbon dioxide (11C]CO2) from the cyclotron target and POCl3 (11.5 equiv.) in diglyme (150 μL) at 20 °C for 4 min, [11C]1 was yielded in modest radiochemical yields (RCY = 63%) (Determined by radio-HPLC analysis of the crude product n.d.) together with the 11C-labelled symmetric urea as a byproduct ([11C]2, RCY = 31% Scheme 1)
Summary
Formamides are common motifs of biologically-active compounds (e.g. formylated peptides) and are frequently employed as intermediates to yield a number of other functional groups. Novel [11C]CO2 direct radiolabelling strategies have been developed based on the electrophilicity of [11C]CO2, significantly improving its applicability as a synthon (Rotstein et al 2013; Dahl et al 2017; Deng et al 2019; Taddei and Gee 2018; Bongarzone et al.2017; Riss et al 2012; Krasikova et al 2009; van der Meij et al 2003) These strategies include the use of: i) highly reactive nucleophiles (e.g. Grignard reagents or organolithium compounds) to form [11C]carboxylic acids (Rotstein et al 2013; Krasikova et al 2009; van der Meij et al 2003); and ii) superbases, known as CO2-fixation agents, for the carboxylation of boronic esters, amines and alcohols (Rotstein et al 2013; Dahl et al 2017; Deng et al 2019; Taddei and Gee 2018; Bongarzone et al 2017; Riss et al 2012). Superbases, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 2-tertbutylimino-2-diethylamino-1, 3-dimethyl-perhydro-1,3,2- diazaphosphorine (BEMP) (Dahl et al 2017; Deng et al 2019; Taddei and Gee 2018; Bongarzone et al 2017), are capable of increasing [11C]CO2 solubility and reactivity by creating labile bonds with [11C]CO2 and have enabled the rapid and reliable synthesis of [11C]carboxylic acids (Riss et al 2012), [11C]amides (Bongarzone et al 2017; Aubert et al 1997), [11C]ureas (Downey et al 2018; Haji Dheere et al 2013), [11C]isocyanates (Wilson et al 2011), [11C]carbonates (Haji Dheere et al 2018)
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