Development of carbon‐11 labelled PET tracers—radiochemical and technological challenges in a historic perspective

Abstract

The development of positron emission tomography (PET) from being an exclusive and expensive research tool at major research institutes to a clinically useful modality found at most major hospitals around the world is largely dependent on radiochemistry and synthesis technology achievements by a few pioneer researchers starting their PET careers 40 to 50 years ago. Especially, the introduction of [(11) C]methyl iodide resulted in a quantum jump in the history of PET tracer development enabling the smooth labelling of a multitude of useful tracers. A more recent and still challenging methodological improvement is transition metal mediated (11) C-carbonylations, having a large synthetic potential that has, however, not yet been realized in the clinical setting. This mini-review focuses on the history of carbon-11 radiochemistry and related technology developments and the role this played in PET tracer developments, especially emphasizing radiolabelling of endogenous compounds. A few examples will be presented of how the use of radiolabelled endogenous substances have provided fundamental information of in vivo biochemistry using the concept of position-specific labelling in different positions in the same molecule.

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

“…3,7,8 [ 11 C]Methyl iodide and [ 11 C]methyl triflate are nowadays readily prepared in many cyclotron-equipped radiochemistry facilities using commercial apparatus. 9 The precursors for 11 C-methylation are typically alcohols, amines, thiols, carboxylates, or amides, which can all be subjected to similar labeling conditions that seldom require significant optimization. The primary variables are the nature and stoichiometry of added base (if needed) and any deprotection and/or workup steps prior to purification.…”

Direct [11C]Methylation of Amines from [11C]CO2 for the Synthesis of PET Radiotracers

“…Methylation reactions of heteroatoms, in particular nitrogen, is one of the more classic approaches used for the 11 C‐labeling of molecules,3a,6 as illustrated by the radiosynthesis of the β‐amyloid imaging radioligand [ 11 C]PIB 9. These radiomethylations require preliminary transformation of 11 CO 2 into very reactive species, 11 CH 3 I or 11 CH 3 OTf 3a,6,10. These reagents are often used under basic conditions in a strictly anhydrous environment.…”

Exploring Metabolism In Vivo Using Endogenous 11 C Metabolic Tracers

“…Their use in 11 C tracers falls into three main categories: methylations, cyanations, and carbonyl chemistry (CO 2 , CO, COCl 2 ). Several excellent reviews have highlighted methods of 11 C incorporation into radiopharmaceuticals(32–35). …”

“…In the heart, oxidative phosphorylation requires that pyruvate be decarboxylated to synthesize acetyl-CoA. When [1- 11 C] pyruvate is decarboxylated, labeling of metabolically inert 11 C-CO 2 results in no tissue retention(35). In contrast, when [3- 11 C] pyruvate is used the label is incorporated into acetyl-CoA for import into mitochondria.…”