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.

O⁶-Benzylguanine (O⁶-BG) is a substrate of O⁶-methylguanine-DNA methyltransferase (MGMT), which is involved in drug resistance of chemotherapy in the majority of glioblastoma multiform. For clinical diagnosis, it is hoped that the MGMT expression level could be determined by a noninvasive method to understand the detailed biological properties of MGMT-specific tumors. We synthesized ¹¹C-labeled O⁶-[(3-methyl)benzyl]guanine ([¹¹C]mMeBG) as a positron emission tomography probe. Thus, a mixed amine-protected stannyl precursor, N⁹-(tert-butoxycarbonyl)-O⁶-[3-(tributylstannyl)benzyl]-N²-(trifluoroacetyl)guanine, was subjected to rapid C-[¹¹C]methylation under [¹¹C]CH₃I/[Pd₂(dba)₃]/P(o-CH₃C₆H₄)₃/CuCl/K₂CO₃ in NMP, followed by quick deprotection with LiOH/H₂O, giving [¹¹C]mMeBG with total radioactivity of 1.34GBq and ≥99% radiochemical and chemical purities.

The nucleosides zidovudine (AZT), stavudine (d4T), and telbivudine (LdT) are approved for use in the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. To promote positron emission tomography (PET) imaging studies on their pharmacokinetics, pharmacodynamics, and applications in cancer diagnosis, a convenient one-pot method for Pd(0)-Cu(I) co-mediated rapid C-C coupling of [(11)C]methyl iodide with stannyl precursor was successfully established and applied to synthesize the PET tracers [(11)C]zidovudine, [(11)C]stavudine, and [(11)C]telbivudine. After HPLC purification and radiopharmaceutical formulation, the desired PET tracers were obtained with high radioactivity (6.4-7.0 GBq) and specific radioactivity (74-147 GBq/µmol) and with high chemical (>99%) and radiochemical (>99.5%) purities. This one-pot Pd(0)-Cu(I) co-mediated rapid C-[(11)C]methylation also worked well for syntheses of [methyl-(11)C]thymidine and [methyl-(11)C]4'-thiothymidine, resulting twice the radioactivity of those prepared by a previous two-pot method. The mechanism of one-pot Pd(0)-Cu(I) co-mediated rapid C-[(11)C]methylation was also discussed.

The most recently discovered serotonin (5-HT) receptor subtype, 5-HT(7), is considered to be associated with several CNS disorders. Noninvasive in vivo positron emission tomography (PET) studies of cerebral 5-HT(7) receptors could provide a significant advance in the understanding of the neurobiology and eventual dysfunctions of the 5-HT(7) receptor. To date, no appropriate 5-HT(7) receptor PET ligand has been developed. Here, we modified known 5-HT(7) selective phenylpiperazinyl-butyloxindole derivatives so that they may be labeled either with carbon-11 or fluorine-18. A set of potential 5-HT(7) ligands for PET molecular imaging was successfully synthesized. Two compounds (10 and 14) were tested against a range of targets. Both compounds display a promising in vitro profile with respect to PET imaging of the 5-HT(7) receptor in thalamic regions.

Uncontrolled proliferation is a fundamental characteristic of cancer, and consequently, imaging of tumor proliferative status finds interest clinically both as a diagnostic tool and for evaluation of response to treatment. Positron emission tomography (PET) radiotracers based on a nucleoside core, such as 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT), have been extensively studied for this purpose. However, [18F]FLT suffers from poor DNA incorporation leading to occasional poor correlation of [18F]FLT tumor uptake with other proliferation indicators such as Ki-67 immunostaining.

N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)thymidine ([18F]2) and N3-((1-(2-[18F]fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-4'-thio-β-thymidine ([18F]3) were synthesized by click chemistry from [18F]fluoroethyl azide and by direct nucleophilic substitution of a tosylate precursor. Metabolic stability and phosphorylation potential of the radiotracers were evaluated in vitro and compared to [18F]FLT. Further, metabolic stability and biodistribution analysis of [18F]2 and [18F]3 were evaluated in vivo.

Stable isotope standards and radiochemistry precursors were synthesized by modification of existing literature procedures. [18F]2 and [18F]3 were synthesized in a radiochemical yield of 8%-12% (end of synthesis, non-decay corrected). Both nucleosides were stable to metabolic degradation by thymidine phosphorylase, and in vivo stability analysis showed only one metabolite for [18F]3. No phosphorylation of [18F]2 could be detected in HCT116 cell homogenates, and in the same assay, only minor (∼8%) phosphorylation of [18F]3 was observed. Biodistribution in Balb/c mice indicated rapid clearance for [18F]2 and [18F]3 to a lesser extent.

The favorable biodistribution and metabolic profile of [18F]3 warrant further investigation as a next-generation PET proliferation marker.