Development of PET radioligands synthesized from in-target produced [11C]methane

Abstract

The aim of this thesis was two-fold. The first aim was to compare the specific radioactivity (SA) of positron emission tomography (PET) radioligands synthesized from in-target produced [11C]methane ([11C]CH4) and [11C]carbon dioxide ([11C]CO2). The second aim was to apply high SA [11C]CH4 in the development of PET radioligands for CNS targets such as the metabotropic glutamate receptor 5 (mGluR5), β-amyloid aggregates and the serotonin 1B (5-HT1B) receptor system. PET is a molecular imaging technique that allows for high sensitivity imaging of particular targets or pathways in a living organism. One of the most commonly used radionuclides is carbon-11 (t1/2 = 20.4 min) since it can be incorporated into many molecules without significant effect of biological activity and in addition the short half life allows for repeated injections in the same subject and day.

The 14N(p, α)11C reaction on N2–O2 or N2–H2 gaseous systems during proton bombardment allows for the production of [11C]carbon dioxide ([11C]CO2) and [11C]methane ([11C]CH4). Compared to the more common in-target produced [11C]CO2, the [11C]CH4 resulted in a mean 6 fold to 17 fold increase of SA for four different PET radioligands synthesized from [11C]methyl iodide ([11C]CH3I). For the dopamine D2 antagonist [11C]raclopride, we obtained an average SA of 3908 GBq/μmol at the end of bombardment for the last 52 productions, which is a 32-fold increase compared to using the [11C]CO2 target. The mean SA of a radioligand synthesized from hydrogen [11C]cyanide ([11C]HCN) was 398 GBq/μmol when produced from the [11C]CH4 target, which is about nine times higher than from [11C]CO2. The reasons for the higher SA can to the greatest extent be attributed to [11C]CO2 being more sensitive to isotopic dilution from CO2 in the air. The hydroxyamidine [11C]Ximelagatran, and the novel mGluR5 radioligand [11C]AR-P135003 were prepared using palladium mediated 11C-cyanation in high yield. There was high brain exposure of [11C]AR-P135003 in cynomolgus monkey with a regional uptake that was in accordance with the known distribution of mGluR5.

The candidate amyloid PET radioligand [11C]AZD2184 was successfully labeled by a two step radiosynthesis. Examination in monkey brain demonstrated sufficient brain exposure of [11C]AZD2184 (2 – 3% of injected dose) with relatively low levels of white matter retention and may thus provide improved contrast compared to currently used PET radioligands for visualization of amyloid plaques.

Eight carboxamide radioligands from three different core structures aimed for visualization of the 5-HT1B receptor were examined by PET in monkey and radiometabolites were measured in plasma. Lipophilicity was a physicochemical property showing relation to brain exposure and non-specific binding. [11C]AZ10419369 was the most promising radioligand, showing high uptake of radioactivity in regions rich in 5-HT1B receptors and low uptake in cerebellum resulting in relatively high binding potentials. The reported development program led to the identification of the first successful PET radioligand for visualization of 5-HT1B receptors in the human brain.

In conclusion, we have shown that in-target produced [11C]CH4 makes it possible for the routine 11C-labeling of PET radioligands with high SA. We utilized [11C]CH3I and [11C]HCN synthesized from in-target produced [11C]CH4 in PET radioligand development programs where high SA radioligands for the mGluR5, β-amyloid and the 5-HT1B were successfully developed.