Recent Developments in Carbon-11 Chemistry and Applications for First-In-Human PET Studies

Abstract

Positron emission tomography (PET) is a molecular imaging technique that makes use of radiolabelled molecules for in vivo evaluation. Carbon-11 is a frequently used radionuclide for the labelling of small molecule PET tracers and can be incorporated into organic molecules without changing their physicochemical properties. While the short half-life of carbon-11 (¹¹C; t_½ = 20.4 min) offers other advantages for imaging including multiple PET scans in the same subject on the same day, its use is limited to facilities that have an on-site cyclotron, and the radiochemical transformations are consequently more restrictive. Many researchers have embraced this challenge by discovering novel carbon-11 radiolabelling methodologies to broaden the synthetic versatility of this radionuclide. This review presents new carbon-11 building blocks and radiochemical transformations as well as PET tracers that have advanced to first-in-human studies over the past five years.

Keywords: Carbon-11; first-in-human; positron emission tomography (PET); radiochemistry; radiotracer.

Scheme 1

Selected carbon-11 labelled building blocks.

Scheme 2

New synthetic strategies for [¹¹C]carboxylic acids [24,28,29,30].

Scheme 3

Synthesis of [¹¹C]carboxylic acids via isotopic exchange [31,32,33].

Scheme 4

[¹¹C]CO₂ fixation, [¹¹C]isocyanate formation and ¹¹C-products.

Scheme 5

Synthesis of [¹¹C]amides and [¹¹C]formamides via [¹¹C]isocyanates [34,35,36,37].

Scheme 6

¹¹C-labelled ureas and carbamates via the Staudinger aza-Wittig reaction [40,41,42].

Scheme 7

Synthesis of carbon-11 labelled benzimidazoles and benzothiazoles [43].

Scheme 8

Synthesis of a [¹¹C]carbonate from [¹¹C]CO₂ (RCY and A_m are base-dependent) [44].

Scheme 9

Ring-opening of non-activated aziridines with [¹¹C]CO₂ [45].

Scheme 10

Recent progress in [¹¹C]CH₃I chemistry [25,61,62,63,64].

Scheme 11

¹¹C-C cross-coupling with [¹¹C]methyllithium [68].

Scheme 12

Production of [¹¹C]hydrogen cyanide from [¹¹C]methyl iodide [72].

Scheme 13

[¹¹C]Fluoroform chemistry [73,74,75].

Scheme 14

[¹¹C]Carbonyl difluoride synthesis and subsequent reaction to cyclic products and linear unsymmetrical ureas [76,77].

Scheme 15

Synthesis of [¹¹C]carbon disulfide and formation of [¹¹C]dithiocarbamate transition metal complexes [81].

Scheme 16

Synthesis of and reactions with ammonium [¹¹C]thiocyanate [83].

Scheme 17

Synthesis of [¹¹C]formaldehyde using XeF₂ as oxidizing agent and reaction to [¹¹C]Me-AIB [85].

Figure 1

Chemical structures of the majority of first-in-human PET tracers labelled with ¹¹C since 2017. Targets, publication years and references of the tracers are listed in Table 1.

Figure 1

Chemical structures of the majority of first-in-human PET tracers labelled with ¹¹C since 2017. Targets, publication years and references of the tracers are listed in Table 1.

Figure 2

Graphical representation of the proportions of ¹¹C-labelling strategies used for FIH PET tracers since 2017.