¹¹C Click Chemistry Using [¹¹C]Methyl Azide: Simplified, Versatile, and Practical Alternative Access to [¹¹C]Nucleosides and [¹¹C]Oligonucleotides for PET Imaging

Abstract

This communication reports the simplified formation of methyl azide and its use in the Huisgen cycloaddition for the rapid, efficient, and selective labeling of modified nucleosides and oligonucleotides. The transposition to radioactive chemistry is presented, and this furnishes practical access to [11C]methylated tracers for positron emission tomography imaging.

11CO bonds made easily for positron emission tomography radiopharmaceuticals

“…In addition to the challenges of selective and rapid isotope incorporation into small molecules, new basic chemistry and applied radiochemistry for preparation and use of these reagents suggests wider dissemination of these techniques for development of both labeling methodologies and novel 11 C-carbonyl radiotracers. Indeed, novel reagents for 11 C-carbonylation, 11 C-cyanation and radiolabeling of alternative functional groups may also be on the horizon, as suggested by recent forays using [ 11 C]methyl azide, 213 [ 11 C]formaldehyde, 214 and [ 11 C]carbon disulfide. 215 Continued advances to these and other methods will streamline in vivo evaluation of labeled compounds, facilitate access to compounds with greater structural diversity, and expand the library of radiopharmaceuticals for PET imaging.…”

Last-Step Pd-Mediated [11C]CO Labeling of a Moxestrol-Conjugated o-Iodobenzyl Alcohol: From Model Experiments to in Vivo Positron Emission Tomography Studies

“…Thus, last-step radiolabeling of biomolecule-based structures has emerged as a powerful strategy, 5,6 and various prosthetic groups have been designed aiming 18 F 7,8 or 11 C labeling. 9,10 In this last case, [ 11 C]CH 3 I, which is obtained in two steps from the cyclotron-produced [ 11 C]CO 2 , has been probably the most investigated 11 Csynthon. 11 Simple alkylations on heteroatoms or moreadvanced strategies based on cross-coupling reactions have been used, but chemo-and regioselectivity issues can occur when dealing with more-complex substrates.…”

“…Starting from a known ligand for a defined biological target, the replacement of a 12 C by its carbon-11 isotope allows identical biodistribution, and fluorine-18 can generally be introduced onto the original structure without significant change in the activity. − However, these approaches are lacking in modularity and often remain poorly compatible with highly functionalized biomolecules (i.e., peptides, oligonucleotides, etc.). Thus, last-step radiolabeling of biomolecule-based structures has emerged as a powerful strategy, , and various prosthetic groups have been designed aiming 18 F , or 11 C labeling. , In this last case, [ 11 C]­CH 3 I, which is obtained in two steps from the cyclotron-produced [ 11 C]­CO 2 , has been probably the most investigated 11 C-synthon . Simple alkylations on heteroatoms or more-advanced strategies based on cross-coupling reactions have been used, but chemo- and regioselectivity issues can occur when dealing with more-complex substrates.…”

“…10.1021/acs.bioconjchem.7b00583.General experimental procedures and spectroscopic data ( 1 H and13 C NMR) for12 C and13 C products. Experimental procedures and radio-HPLC traces for11 C products and in vivo experiments.…”

General Last-Step Labeling of Biomolecule-Based Substrates by [12C], [13C], and [11C] Carbon Monoxide

“…For all these reasons, mild and specific ligation of the radioactive synthon to a synthetic building block linked to the biomolecule is particularly attractive. Indeed this strategy has been applied for many radioelements by covalent binding or chelation and often proved to be successful for PET imaging with 11 C or other radionuclides (Figure ). However, carbon monoxide has never been used as an isotopic carbon source for such an approach despite numerous advantages.…”