Alternative methods for making [11C]amides - Application to the preparation of 5-HT1A receptor radioligands

Full text: The amide group is widely found in drug-like ligands for neurotransmitter receptors from which radioligands are developed for imaging these receptors in brain with positron emission tomography (PET), either in clinical research or drug development. An important consideration for radioligand development is the position at which a positron-emitting radioistope, frequently carbon-11 (t1/2 = 20.4 min), should be introduced into the ligand in order to avoid radioactive metabolites that may enter brain with the undesirable possibility to confound PET measurements of radioligand binding to the target receptor. Amides are often metabolized by simple hydrolysis in the liver to produce the parent amine and carboxylic acid in the blood. Generally, simple carboxylic acids, because they are ionized at physiological pH do not enter brain to a great extent, whereas the brain penetration of amines is subject to many factors. Hence, for a potential PET radioligand containing an amide linkage, introduction of a carbon-11 label on the carbonyl side of the amide bond, and even in the carbonyl entity, may be preferred. This is so for imaging brain 5-HT1A receptors with 11C-labeled WAY-100635. Such considerations create a need for effective methods for labeling amides in the carbonyl group with cyclotron-produced carbon-11. Various methods have been developed during the last two decades, and these methods will be surveyed here together with their previous and ongoing application to the preparation of antagonist- and agonist-type PET radioligands for 5-HT1A receptors. (author)