Positron emission tomography (PET) is a powerful and rapidly developing area of molecular imaging that is used to study and visualize human physiology by the detection of positron-emitting radiopharmaceuticals. Information about metabolism, receptor/enzyme function, and biochemical mechanisms in living tissue can be obtained directly from PET experiments. Unlike magnetic resonance imaging (MRI) or computerized tomography (CT), which mainly provide detailed anatomical images, PET can measure chemical changes that occur before macroscopic anatomical signs of a disease are observed. PET is emerging as a revolutionary method for measuring body function and tailoring disease treatment in living subjects. The development of synthetic strategies for the synthesis of new positron-emitting molecules is, however, not trivial. This Review highlights key aspects of the synthesis of PET radiotracers with the short-lived positron-emitting radionuclides (11)C, (18)F, (15)O, and (13)N, with emphasis on the most recent strategies.

Synthesis of 11C, 18F, 15O, and 13N Radiolabels for Positron Emission Tomography

Anatomy of SUV

The regional distributions of monoamine oxidase (MAO) types A and B have been identified in human brain in vivo with intravenously injected 11C-labeled suicide enzyme inactivators, clorgyline and L-deprenyl, and positron emission tomography. The rapid brain uptake and retention of radioactivity for both 11C tracers indicated irreversible trapping. The anatomical distribution of 11C paralleled the distribution of MAO A and MAO B in human brain in autopsy material. The corpus striatum, thalamus, and brainstem contained high MAO activity. The magnitudes of uptake of both [11C]clorgyline and L-[11C]deprenyl were markedly reduced in one subject treated with the antidepressant MAO inhibitor phenelzine. A comparison of the brain uptake and retention of the 11C-labeled inactive (D-) and active (L-) enantiomers of deprenyl showed rapid clearance of the inactive enantiomer and retention of the active enantiomer within MAO B-rich brain structures, in agreement with the known stereoselectivity of MAO B for L-deprenyl. Prior treatment with unlabeled L-deprenyl prevented retention of L-[11C]deprenyl. Thus, suicide enzyme inactivators labeled with positron emitters can be used to quantitate the distribution and kinetic characteristics of MAO in human brain structures.

https://science.sciencemag.org/content/sci/235/4787/481.full.pdf

Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET.

Cancer cells show increased metabolism of both glucose and amino acids, which can be monitored with 18F-2-deoxy-2-fluoro-D-glucose (FDG), a glucose analogue, and 11C-L-methionine (Met), respectively. FDG uptake is higher in fast-growing than in slow-growing tumors. FDG uptake is considered to be a good marker of the grade of malignancy. Several studies have indicated that the degree of FDG uptake in primary lung cancer can be used as a prognostic indicator. Differential diagnosis of lung tumors has been studied extensively with both computed tomography (CT) and positron emission tomography (PET). It has been established that FDG-PET is clinically very useful and that its diagnostic accuracy is higher than that of CT. Detection of lymph node or distant metastases in known cancer patients using a whole-body imaging technique with FDG-PET has become a good indication for PET. FDG uptake may be seen in a variety of tissues due to physiological glucose consumption. Also FDG uptake is not specific for cancer. Various types of active inflammation showed FDG uptake to a certain high level. Understanding of the physiological and benign causes of FDG uptake is important for accurate interpretation of FDG-PET. In monitoring radio/chemotherapy, changes in FDG uptake correlate with the number of viable cancer cells, whereas Met is a marker of proliferation. Reduction of FDG uptake is a sensitive marker of viable tissue, preceding necrotic extension and volumetric shrinkage. FDG-PET is useful for the detection of recurrence and for monitoring the therapeutic response of tumor tissues in various cancers, including those of the lung, colon, and head and neck. Thus, PET, particularly with FDG, is effective in monitoring cancer cell viability, and is clinically very useful for the diagnosis and detection of recurrence of lung and other cancers.

From tumor biology to clinical Pet: a review of positron emission tomography (PET) in oncology.

The utilization of CO2 as a soft oxidant and promoter is a promising concept for industrial applications that could not only contribute to the mitigation of CO2 levels, but also the development of economical and energy efficient syntheses of various chemicals. The abundant availability, non-toxic, economic and mild oxidizing properties of CO2 has resulted in immense interest in its use as an oxidant in several reactions, such as the oxidative coupling of CH4 and the oxidative dehydrogenation of alkanes and alkyl aromatics. At present, only a few processes based on CO2 as a soft oxidant have been realised on a technical scale in spite of dedicated research. This review is intended to trace the emergence, application and understanding of such systems and shed light on the further development that may lead to industrial scale operations in the near future.

Carbon dioxide utilization as a soft oxidant and promoter in catalysis

Optimization of [11C]HCN production and no-carrier-added [1-11C]amino acid synthesis

[18F]fluoride production with a circulating [18O]water target

Abstract [ 18 F]fluoride was produced via the 18 O(p,n) 18 F reaction with a circulating 20% enriched [ 18 O]water target. Parameters affecting the production yield of [ 18 F]fluoride such as beam current, beam profile, irradiation time, target thickness, circulation rate, and window material were investigated and optimized. With a 20 μA irradiation of 2.5 mL [ 18 O]water circulated at a flow rate of over 35 mL/min, a [ 18 F]fluoride yield of more than 70% was obtained when the beam was defocussed and wobbled to get a uniform beam profile. In addition, radiolytically produced gases were recombined using a Pd catalyst into the target.

[18F]Fluoride Production with a Circulating [18O]Water Target

Carbon-11 (11C) pargyline, which is a suicide inactivator of Type B monoamine oxidase (MAO), was synthesized by the reaction of N-demethylpargyline with 11CH3I. Biodistribution was investigated in mice, and positron tomographic images of the heart and lung in a rabbit were obtained. The distribution of 11C after administration of [11C]pargyline was measured in several organs and blood at various time intervals. After 30 min its concentrations in the organs were constant. Subcellular distribution studies in the brain, lung, liver, and kidney showed that 59-70% of the 11C became acid-insoluble and 9-33% was present in the crude mitochondrial fraction at 60 min after injection. However, a high loading dose influenced the subcellular distribution but had little effect on tissue distribution. The uptakes of the 11C in each organ except for the kidney and spleen seemed to correlate with the in vitro enzymatic activity of Type B MAO. At high loading dose a nonspecific uptake was observed.

Biodistribution of a positron-emitting suicide inactivator of monoamine oxidase, carbon-11 pargyline, in mice and a rabbit.

The myocardial uptake of 18F-FDG was investigated under various conditions, and compared with brain and tumor uptake as a function of blood glucose level. The uptake by the heart of normal feeding rats was rapid and remained essentially unchanged up to 2 h after 18F-FDG injection, approximately 3%-4% dose/g tissue. On the other hand, the myocardial uptake of fasted rats was significantly lower than that of control rats throughout the course of the study, and it was about 0.3%-0.4% dose/g tissue. Myocardial uptake of 18F-FDG was relatively constant at glucose levels under about 120 mg/100 ml and increased steeply at higher blood glucose levels. In contrast, brain uptake decreased linearly with increasing levels of blood glucose, revealing a strong negative correlation between brain uptake of 18F-FDG and blood glucose levels. The tumor uptake pattern remained relatively unchanged, irrespective of blood glucose levels. It was revealed that the glucose demands of brain, heart, and tumor were entirely different. After a glucose load, the myocardial uptake of fasted rats increased only slightly from 0.4% to 0.6% dose/g tissue, in spite of transitional hyperglycemia. In contrast, insulin caused myocardial uptake to increase extraordinarily, although it caused a decrease in blood glucose levels.

Ren Iwata

Papers

Optimization of [11C]HCN production and no-carrier-added [1-11C]amino acid synthesis

[18F]fluoride production with a circulating [18O]water target

[18F]Fluoride Production with a Circulating [18O]Water Target

Biodistribution of a positron-emitting suicide inactivator of monoamine oxidase, carbon-11 pargyline, in mice and a rabbit.

Experimental studies on myocardial glucose metabolism of rats with 18F-2-fluoro-2-deoxy-D-glucose.