Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds

Abstract

The presence of positron emission tomography (PET) centers at most major hospitals worldwide, along with the improvement of PET scanner sensitivity and the introduction of total body PET systems, has increased the interest in the PET tracer development using the short-lived radionuclides carbon-11. In the last few decades, methodological improvements and fully automated modules have allowed the development of carbon-11 tracers for clinical use. Radiolabeling natural compounds with carbon-11 by substituting one of the backbone carbons with the radionuclide has provided important information on the biochemistry of the authentic compounds and increased the understanding of their in vivo behavior in healthy and diseased states. The number of endogenous and natural compounds essential for human life is staggering, ranging from simple alcohols to vitamins and peptides. This review collates all the carbon-11 radiolabeled endogenous and natural exogenous compounds synthesised to date, including essential information on their radiochemistry methodologies and preclinical and clinical studies in healthy subjects.

A Medicinal Chemistry Perspective on Excitatory Amino Acid Transporter 2 Dysfunction in Neurodegenerative Diseases

“…Although the use of PET radiolabeled glutamate (e.g., [ 11 C]glutamate) may work to investigate neurotransmitter trafficking and availability of its transporters/receptors, it would lack of selectivity and potentially be converted to glutamine, confounding imaging results. 19,20 Note that there are no brain-penetrant EAAT2- selective PET radiotracers available for clinical research (an early phase 1 EAAT2 targeted positron emitting agent, [ 18 F]fluorenylasparaginate methyl ester -[ 18 F]RP-115 -started to recruit on May 2022 for which no published data are available yet, clinical trials: NCT05374378). The initial step for developing a PET radiotracer targeting EAAT2 should be the selection of a molecule with high affinity and selectivity toward EAAT2.…”

“…Minimal invasive neuroimaging techniques, such as positron emission tomography (PET), are key to evaluate neurotransmitter trafficking and transporter density. Although the use of PET radiolabeled glutamate (e.g., [ 11 C]­glutamate) may work to investigate neurotransmitter trafficking and availability of its transporters/receptors, it would lack of selectivity and potentially be converted to glutamine, confounding imaging results. , Note that there are no brain-penetrant EAAT2-selective PET radiotracers available for clinical research (an early phase 1 EAAT2 targeted positron emitting agent, [ 18 F]­fluorenylasparaginate methyl ester - [ 18 F]­RP-115 - started to recruit on May 2022 for which no published data are available yet, clinical trials: NCT05374378).…”

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

“…[ 11 C]Carbon monoxide has gained much interest in recent years. Novel 11 CO-chemistry will not be covered within this review but we refer to recent comprehensive reviews of [ 11 C]CO production methods and 11 C-carbonylation chemistry [ 46 , 47 , 48 , 49 , 50 ]. Although many straightforward routes for [ 11 C]CO production have been established, and a diverse portfolio of [ 11 C]carbonylation reactions has been developed, this branch of carbon-11 chemistry is still heavily underrepresented in PET tracer synthesis.…”

Reactive Palladium–Ligand Complexes for 11C-Carbonylation at Ambient Pressure: A Breakthrough in Carbon-11 Chemistry

“…Labeling with carbon-11 can thus be achieved without altering the physicochemical or pharmacological properties of a compound. Carbon-11 is generally produced with a cyclotron using a high-energy proton bombardment of nitrogen gas according to the 14 N(p, α) 11 C nuclear reaction [7][8][9][10]. The two major 11 C-labeled primary precursors, [ 11 [6].…”

“…Labeling with carbon-11 can thus be achieved without altering the physicochemical or pharmacological properties of a compound. Carbon-11 is generally produced with a cyclotron using a high-energy proton bombardment of nitrogen gas according to the 14 N(p, α) 11 C nuclear reaction [ 7 , 8 , 9 , 10 ]. The two major 11 C-labeled primary precursors, [ 11 C]carbon dioxide ([ 11 C]CO 2 ) and [ 11 C]methane ([ 11 C]CH 4 ), are formed, respectively, when either small amounts of oxygen (0.1–2%) or hydrogen (5–10%) are present in the target.…”