"In-loop" carbonylation-A simplified method for carbon-11 labelling of drugs and radioligands

Abstract

Transition-metal mediated carbonylation with ¹¹ C-labelled carbon monoxide ([¹¹ C]CO) is a versatile method for introducing ¹¹ C (t_1/2 = 20.3 min) into drugs and radioligands for subsequent use in positron emission tomography (PET). The aim of the current study was to perform the ¹¹ C-carbonylation reaction on the interior surface of a stainless-steel loop used for high performance liquid chromatography (HPLC). In the experimental setup, cyclotron produced ¹¹ C-labelled carbon dioxide ([¹¹ C]CO₂ ) was converted to [¹¹ C]CO by reduction over heated Molybdenum and swept into an HPLC loop pre-charged with the appropriate reaction mixture. Following a 5 min reaction, the radiochemical purity (RCP) and the trapping efficiency (TE) of the reaction mixture was determined. After optimization, [¹¹ C]N-Benzylbenzamide was obtained in quantitative radiochemical yield (RCY) following a 5 min reaction at room temperature. The methodology was further applied to label [¹¹ C]benzoic acid (RCP≥99%, TE>91%), [¹¹ C]methyl benzoate (RCP≥99%, TE>93%) and [¹¹ C]phthalide (RCP≥99%, TE>88%). A set of pharmaceuticals was finally radiolabelled using non-optimized conditions. Excellent yields were obtained for the histamine-3 receptor radioligand [¹¹ C]AZ13198083, the oncology drug [¹¹ C]olaparib and the dopamine D2 receptor radioligand [¹¹ C]raclopride, whereas a moderate yield was observed for the high-affinity dopamine D2 receptor radioligand [¹¹ C]FLB457. The presented "in-loop" process proved efficient for diverse ¹¹ C-carbonylations, providing [¹¹ C]amides, [¹¹ C]esters and [¹¹ C]carboxylic acids in moderate to excellent RCYs. Based on the advantages associated with performing the radiolabelling step as an integrated part of the purification system, this methodology may become a valuable addition to the toolbox of methodologies used for ¹¹ C-carbonylation of drugs and radioligands for PET.

Keywords: 11C-carbonylation; carbon-11; loop; radioligands; radiopharmaceutical chemistry.

Figure 1

Schematic representation of the HPLC loop applied in the ¹¹C‐carbonylation procedure. The yellow arrows indicate the flow direction for [¹¹C]CO

Figure 2

Picture (left) and autoradiographical image (right) of the HPLC loop following entrapment of [¹¹C]CO in the synthesis of [¹¹C]N‐benzylbenzamide. The arrows indicate the entry and exit points of the He carrier gas through the HPLC loop

Scheme 1

Synthesis of [¹¹C]phthalide, [¹¹C]methyl benzoate and [¹¹C]benzoic acid, via “in‐loop” ¹¹C‐carbonylation.

Scheme 2

“In‐loop” ¹¹C‐carbonylation applied to four drug‐like molecules.