Exploring Metabolism In Vivo Using Endogenous 11 C Metabolic Tracers

Abstract

Cancer and other diseases are increasingly understood in terms of their metabolic disturbances. This thinking has revolutionized the field of ex vivo metabolomics and motivated new approaches to detect metabolites in living systems including proton magnetic resonance spectroscopy (1H-MRS), hyperpolarized 13C MRS, and positron emission tomography (PET). For PET, imaging abnormal metabolism in vivo is hardly new. Positron-labeled small-molecule metabolites have been used for decades in humans, including 18F-FDG, which is used frequently to detect upregulated glycolysis in tumors. Many current 18F metabolic tracers including 18F-FDG have evolved from their 11C counterparts, chemically identical to endogenous substrates and thus approximating intrinsic biochemical pathways. This mimicry has stimulated the development of new radiochemical methods to incorporate 11C and inspired the synthesis of a large number of 11C endogenous radiotracers. This is in spite of the 20-minute half-life of 11C, which generally limits its use in patients to centers with an on-site cyclotron. Innovation in 11C chemistry has persisted in the face of this limitation, because (1) the radiochemists involved are inspired (2) the methods of 11C incorporation are diverse and (3) 11C compounds often show more predictable in vivo behavior, thus representing an important first step in the validation of new tracer concepts. In this mini-review we will discuss some of the general motivations behind PET tracers, rationales for the use of 11C, and some of the special challenges encountered in the synthesis of 11C endogenous compounds. Most importantly, we will try to highlight the exceptional creativity employed in early 11C tracer syntheses, which used enzyme-catalyzed and other “green” methods before these concepts were commonplace.

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

“…Methionine is a sulfur-containing amino acid that can be rapidly synthesized without complicated purification steps . Numerous synthetic pathways can be used based on the alkylation of the corresponding sulfide anion of l -homocysteine with either [ 11 C]­CH 3 I (Figure ) or [ 11 C]­CH 3 OTf . Moreover, l -[ methyl - 11 C]­methionine can be efficiently produced by 11 C-methylation of l -cysteine thiolactone hydrochloride or l -homocysteine in solution using the “bubbling” method, on a solid-phase extraction cartridge or by using the captive solvent method (“in the loop”) with or without semipreparative HPLC purification.…”

Small Molecule Sensors Targeting the Bacterial Cell Wall

“…For 11 C metabolites, structures can be generated that are chemically identical to those of their parent molecules. 27 This strategy is also a key feature of the most commonly used PET radiotracer, [ 18 F]FDG, which is a substrate for both glucose transporters (GLUTs) and hexokinase. Many radionuclides have been used to image infection, including 11 C (PET, t 1/2 = 20 min), 68 Ga (PET, t 1/2 = 68 min), 18 F (PET, t 1/2 = 110 min), 99m Tc (SPECT, t 1/2 = 6 h), 64 Cu (PET, t 1/2 = 13 h), 111 In (SPECT, t 1/2 = 67 h), 201 Tl (t 1/2 = 73 h), 67 Ga (SPECT, t 1/2 = 78 h), With respect to the bacterial cell wall, several recent studies have demonstrated the synergy of optical and nuclear imaging.…”

“…This is particularly true for 11 C and 18 F radionuclei for which substitution likely induces fewer perturbations of biologic behavior. For 11 C metabolites, structures can be generated that are chemically identical to those of their parent molecules . This strategy is also a key feature of the most commonly used PET radiotracer, [ 18 F]­FDG, which is a substrate for both glucose transporters (GLUTs) and hexokinase.…”

Nuclear Imaging of Glucose Metabolism: Beyond 18F-FDG

“…Because carbon is a component of biomolecules, labeling with the positron-emitting radioisotope carbon-11 ( 11 C) seems to be very attractive. Many attempts have been made to label glucose with radioisotope 11 C [60, 61]. [2- 11 C]-2-Deoxyglucose was developed as the 11 C counterpart of 18 F-FDG [62].…”