Synthesis of Radiopharmaceuticals via “In-Loop” 11C-Carbonylation as Exemplified by the Radiolabeling of Inhibitors of Bruton's Tyrosine Kinase

Abstract

Positron emission tomography (PET) is an important non-invasive tool to help guide the drug discovery and development process. Positron-emitting–radiolabeled drug candidates represent an important tool for drug hunters to gain insight into a drug's biodistribution and target engagement of exploratory biologic targets of interest. Recently, there have been several drug candidates that incorporate an acryloyl functional group due to their ability to form a covalent bond within the biological target of interest through Michael addition. Methods to incorporate a carbon-11 radionuclide into acrylamide derivatives remain challenging given the reactive nature of this moiety. Herein, we report the improved radiosynthesis of carbon-11–containing acrylamide drug candidates, [11C]ibrutinib, [11C]tolebrutinib, and [11C]evobrutinib, using [11C]CO and a novel “in-loop” 11C-carbonylation reaction. [11C]Ibrutinib, [11C]tolebrutinib, and [11C]evobrutinib were reliably synthesized, generating 2.2-7.1 GBq of these radiopharmaceuticals in radiochemical yields ranging from 3.3 to 12.8% (non-decay corrected; relative to starting [11C]CO2) and molar activities of 281-500 GBq/μmol (7.5-13.5 Ci/μmol), respectively. This study highlights an improved method for incorporating carbon-11 into acrylamide drug candidates using [11C]CO within an HPLC loop suitable for clinical translation using simple modifications of standard automated synthesis modules used for cGMP manufacture of PET radioligands.

Strategies for the Production of [11C]LY2795050 for Clinical Use

“…In addition, we compare radiocyanation methods A−C with a Pdmediated radiocarbonylation strategy (method D) (Figure 3). 13 This latter approach eliminates the need for nitrile hydrolysis following 11 C radiolabeling. Method A: Cu(OTf) 2 -Mediated Radiocyanation of Aryl−Bpin Precursor 1.…”

“…The first utilizes the Cu-mediated radiocyanation of a boronate ester precursor followed by nitrile hydrolysis (method A ) . The other three employ an aryl iodide precursor for Pd- , (method B ) or Cu-mediated (method C ) radiocyanation or for Pd-mediated radiocarbonylation (method D ) . Automation of method A has been described previously by our group, while method B , originally described by colleagues at the Yale PET Center, has not been automated to our knowledge.…”

“…11 The other three employ an aryl iodide precursor for Pd- 4,7 (method B) or Cumediated 12 (method C) radiocyanation or for Pd-mediated radiocarbonylation (method D). 13 Automation of method A has been described previously by our group, while method B, originally described by colleagues at the Yale PET Center, has not been automated to our knowledge. Methods C and D have not previously been applied to the synthesis of [ 11 C]-LY2795050 prior to this work.…”

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

“…This has now been overcome with systems such as the TracerMaker TM which is used by our laboratories for the syntheses of N -[ 11 C]acrylamide PET tracers for imaging Bruton’s tyrosine kinase via a palladium-NiXantphos-mediated carbonylation using [ 11 C]CO [ 51 , 52 ]. The synthesis of the same class of compounds has also recently been automated as “in-loop” procedure using the GE TracerLab synthesis modules [ 53 ]. Prior to this recent work, 11 C-labelled N -acrylamides were synthesized from [ 11 C]acrylic acid or [ 11 C]acryloyl chloride (formed by carboxylation of Grignard or organolithium reagents with [ 11 C]CO 2 ) and were not suitable for human translation.…”

Efficient and Practical Radiosynthesis of Novel [131I]-Xanthine and [131I]-Hypoxanthine

“…Some radionuclides such as iodine-131, iodine-125, technetium-99m, fluorine-18, gallium-68, and carbon-11 have been used for labeling numerous active compounds for their in vitro and in vivo biomedical applications [6,[8][9][10][11][12][13]. Among them, radioiodines are very useful for labeling bioactive molecules containing phenol or imidazole groups [14].…”