¹¹CO bonds made easily for positron emission tomography radiopharmaceuticals

Abstract

The positron-emitting radionuclide carbon-11 (11C, t1/2 = 20.3 minutes) possesses the unique potential for radiolabeling of any biological, naturally occurring, or synthetic organic molecule for in vivo positron emission tomography (PET) imaging. Carbon-11 is most often incorporated into small molecules by methylation of alcohol, thiol, amine or carboxylic acid precursors using [11C]methyl iodide or [11C]methyl triflate (generated from [11C]CO2). Consequently, small molecules that lack an easily substituted 11C-methyl group are often considered to have non-obvious strategies for radiolabeling and require a more customized approach. [11C]Carbon dioxide, [11C]carbon monoxide, [11C]cyanide, and [11C]phosgene represent alternative carbon-11 reactants to enable 11C-carbonylation. Methodologies developed for preparation of 11C-carbonyl groups have had a tremendous impact on the development of novel PET radiopharmaceuticals and provided key tools for clinical research. 11C-Carbonyl radiopharmaceuticals based on labeled carboxylic acids, amides, carbamates, and ureas now account for a substantial number of important imaging agents that have seen translation to higher species and clinical research of previously inaccessible targets, which is a testament to the creativity, utility, and practicality of the underlying radiochemistry.

New methodologies for the preparation of carbon-11 labeled radiopharmaceuticals

“…The innovative method, that was inspired by the recent advances in “green chemistry” and reported in 2009, uses sub-milligram amounts of precursor compound, reacts at low temperature (typically room temperature), for 1–3 min reaction time and does not require advanced technical equipment [34, 35]. To overcome the low reactivity of CO 2 , organic amines such as DBU or BEMP act as organomediators by activating CO 2 prior to the covalent bond formation [36, 37]. The first report on 11 CO 2 fixation was on the synthesis of 11 C-labeled carbamates.…”

[11C]Cyanation of arylboronic acids in aqueous solutions

“…2, 3 Carbon-11-labeled radiotracers are predominantly prepared by methylation reactions between –OH, –NH, or –SH groups and [ 11 C]CH 3 I 4, 5 or [ 11 C]CH 3 OTf. 6 Driven by the need to expand beyond 11 C-methylation reactions as a mainstay in PET radiopharmaceutical production, continued efforts to employ a more diverse library of 11 C-synthons remain a focus for several research laboratories, 7–12 and this topic has been reviewed by us 13–15 and others. 16 We are particularly interested in the development of new [ 11 C]HCN-labeling methods because nitriles are not only frequently present in biologically active agents but also represents a versatile functional group that can be readily converted to 11 C-labeled amides, carboxylic acids or amines.…”

“…16 We are particularly interested in the development of new [ 11 C]HCN-labeling methods because nitriles are not only frequently present in biologically active agents but also represents a versatile functional group that can be readily converted to 11 C-labeled amides, carboxylic acids or amines. 15 Historically, nucleophilic 11 C-cyanation of aliphatic substrates was a subject that received long-term attention and is generally performed via the Strecker reaction 7 or by ring-opening of activated aziridines. 17 The resulting 11 C-labeled aliphatic nitriles have been used to prepare 11 C-labeled amino acids such as [ 11 C]phenylalanine, 18 [ 11 C]tyrosine, 18 and [ 11 C]aspartic acid (Fig.…”

Instantaneous Conversion of [11C]CO2 to [11C]CO via Fluoride‐Activated Disilane Species

“…Among these, [ 11 C]CO can be used to produce a vast array of [carbonyl‐ 11 C]‐containing molecules, for example [ 11 C]ureas, [ 11 C]amides, [ 11 C]esters, [ 11 C]carboxylic acids 1d, 3. These classes of compounds are of great interest as potential radiotracers for molecular imaging applications using positron emission tomography (PET) which allows the quantitative bio‐distribution and kinetics of the labelled compounds to be studied in vivo 4…”