Late-stage 11C-carbonylation of drug-like molecules for PET

Positron emission tomography (PET) is a non-invasive in vivo imaging technique used for translational biomedical research and clinical diagnosis. A fundamental pre-condition for PET is the radiolabelled tracer molecule used in the emission measurement, and there is a pressing need to accelerate the development of novel PET tracers to meet an increasing demand from the healthcare system, academia and drug industry. A cornerstone in this effort is access to methodologies for late-stage isotopic labelling of small molecules with the positron-emitting radionuclide carbon-11 (11C, half-life 20.4 min).

The carbonyl group is one of the most abundant motifs in biologically important molecules and therefore a good target for isotopic labelling. The aim of this thesis was to develop 11Ccarbonylation reactions that made use of [11C]carbon dioxide ([11C]CO2), a synthon obtained directly from medical cyclotrons. The incorporation of this radiolabelled synthon, first into model compounds and later into biologically relevant molecules, was accomplished in automated radiochemistry systems and analysed using liquid chromatography.

Papers I and II describe the development of two different methods for the synthesis of 11Clabelled cyclic ureas. In Paper I, the noteworthy concept of CO2 fixation with strong, organic bases was applied. A set of [11C]benzimidazolones was thus radiolabelled with high radiochemical yields under mild conditions. In Paper II, the task was approached by using a click chemistry-inspired Staudinger/aza-Wittig cascade reaction. A wide selection of five and six-membered cyclic ureas was radiolabelled using this simple one-pot reaction. As a proof of concept, the β-adrenergic radioligand, (S)-[11C]CGP12177, was eventually produced using both methods. Paper III showcased a novel 12C/11C isotopic exchange reaction for labelling of phenylacetic acids. The method is based on heat-induced decarboxylation of the substrate molecule, followed by introduction of isotope-labelled [11C]CO2, without need for any additional reagents. Three small molecules, including two anti-inflammatory drugs, were labelled to prove suitability of the method for a low-concentration carbon-11 source. In Paper IV, the CO2 fixation concept was applied to the preparation of 11C-labelled oxazolidinones and other cyclic urethanes, starting from corresponding anilines, benzylamines and dibromoalkanes. Five and six-membered cyclic urethanes, as well as both phenylic and benzylic compounds, were labelled with moderate to excellent radiochemical yields.

In conclusion, a set of new methodologies was developed for the 11C-labelling of carbonyl groups. Each of the novel methodologies utilised [11C]CO2 obtained directly from a medical cyclotron without further chemical manipulation, and were successfully used in the preparation of cyclic ureas, benzoxazolone and benzothiazolone compounds, phenylacetic acids, Naryloxazolidinones, N-aryloxazinanones and N-benzyloxazinanones. Given the useful radiochemical yields and operational simplicity of these methods, there is a reason to be optimistic about their adoption in future PET tracer development.

List of scientific papers

I. Horkka, K.; Dahl, K.; Bergare, J.; Elmore, C. S.; Halldin, C.; Schou, M. Rapid and efficient synthesis of 11C‐labeled benzimidazolones using [11C]carbon dioxide. ChemistrySelect. 2019, 4, 1846-1849.
https://doi.org/10.1002/slct.201803561

II. Del Vecchio, A.; Caillé, F.; Chevalier, A.; Loreau, O.; Horkka, K.; Halldin, C.; Schou, M.; Camus, N.; Kessler, P.; Kuhnast, B.; Taran, F.; Audisio, D. Late-stage isotopic carbon labeling of pharmaceutically relevant cyclic ureas directly from CO2. Angew Chem Int Ed Engl. 2018, 57, 9744-9748.
https://doi.org/10.1002/anie.201804838

III. Destro, G.; Horkka, K.; Loreau, O.; Buisson, D.-A.; Kingston, L.; Del Vecchio, A.; Schou, M.; Elmore, C. S.; Taran, F.; Cantat, T.; Audisio, D. Transition‐metal‐free carbon isotope exchange of phenyl acetic acids. Angew Chem Int Ed Engl. 2020, 59, 13490-13495.
https://doi.org/10.1002/anie.202002341

IV. Horkka, K.; Mannisto, J. K.; Repo, T.; Schou, M. Late-stage radiolabeling of N-aryl oxazolidinones and other cyclic urethanes starting from [11C]carbon dioxide. [Manuscript]