Purpose
This short review aims to cover the more recent and promising developments of carbon-11 (
11
C) labeling radiochemistry and its utility in the production of novel radiopharmaceuticals, with ...special emphasis on methods that have the greatest potential to be translated for clinical positron emission tomography (PET) imaging.
Methods
A survey of the literature was undertaken to identify articles focusing on methodological development in
11
C chemistry and their use within novel radiopharmaceutical preparation. However, since
11
C-labeling chemistry is such a narrow field of research, no systematic literature search was therefore feasible. The survey was further restricted to a specific timeframe (2000–2016) and articles in English.
Results
From the literature, it is clear that the majority of
11
C-labeled radiopharmaceuticals prepared for clinical PET studies have been radiolabeled using the standard heteroatom methylation reaction. However, a number of methodologies have been developed in recent years, both from a technical and chemical point of view. Amongst these, two protocols may have the greatest potential to be widely adapted for the preparation of
11
C-radiopharmaceuticals in a clinical setting. First, a novel method for the direct formation of
11
C-labeled carbonyl groups, where organic bases are utilized as
11
Ccarbon dioxide-fixation agents. The second method of clinical importance is a low-pressure
11
C-carbonylation technique that utilizes solvable xenon gas to effectively transfer and react
11
Ccarbon monoxide in a sealed reaction vessel. Both methods appear to be general and provide simple paths to
11
C-labeled products.
Conclusion
Radiochemistry is the foundation of PET imaging which relies on the administration of a radiopharmaceutical. The demand for new radiopharmaceuticals for clinical PET imaging is increasing, and
11
C-radiopharmaceuticals are especially important within clinical research and drug development. This review gives a comprehensive overview of the most noteworthy
11
C-labeling methods with clinical relevance to the field of PET radiochemistry.
A transition‐metal‐free carbon isotope exchange procedure on phenyl acetic acids is described. Utilizing the universal precursor CO2, this protocol allows the carbon isotope to be inserted into the ...carboxylic acid position, with no need of precursor synthesis. This procedure enabled the labeling of 15 pharmaceuticals and was compatible with carbon isotopes 14C and 13C. A proof of concept with 11C was also obtained with low molar activity valuable for distribution studies.
Just labeled: Transition‐metal‐free carbon isotope exchange on phenyl acetic acids is described. Utilizing the universal precursor CO2, the carbon isotope can be inserted into the carboxylic acid position, with no need of precursor synthesis. This procedure enabled the labeling of 15 pharmaceuticals and was compatible with 14C and 13C. A proof of concept with 11C was also obtained with low molar activity valuable for distribution studies.
The palladium‐catalyzed 11Ccarbonylation of aryl halides and triflates was achieved at atmospheric pressure by employing xantphos as the supporting ligand. Aryl halides were converted into their ...corresponding 11Camides in good to excellent yields. The conditions were also successfully employed in the radiolabeling of an 11Cester, a 11Ccarboxylic acid, an 11Caldehyde, and a 11Cketone.
The palladium‐catalyzed 11Ccarbonylation of aryl halides and triflates was achieved at atmospheric pressure by employing xantphos as the supporting ligand. Aryl halides were converted into their corresponding 11Camides in good to excellent yields. The conditions were also successfully employed in the radiolabeling of an 11Cester, a 11Ccarboxylic acid, an 11Caldehyde, and a 11Cketone.
The Pd–Xantphos-mediated 11C-carbonylation protocol (also known as the “Xantphos- method”), due to its simplistic and convenient nature, has facilitated researchers in meeting a longstanding need for ...preparing 11C-carbonyl-labeled radiopharmaceuticals at ambient pressure for positron emission tomography (PET) imaging and drug discovery. This development could be viewed as a breakthrough in carbon-11 chemistry, as evidenced by the rapid global adoption of the method by the pharmaceutical industry and academic laboratories worldwide. The method has been fully automated for the good manufacturing practice (GMP)-compliant production of novel radiopharmaceuticals for human use, and it has been adapted for “in-loop” reactions and microwave technology; an impressive number of 11C-labeled compounds (>100) have been synthesized. Given the simplicity and efficiency of the method, as well as the abundance of carbonyl groups in bioactive drug molecules, we expect that this methodology will be even more widely adopted in future PET radiopharmaceutical research and drug development.
Radiometabolite corrected arterial plasma input function is essential for quantitative measurement of the brain binding of positron emitting radioligands and drugs that have no suitable reference ...region in brain. Various sample preparation techniques have been successfully applied for extraction of radioligands and their metabolites from biological samples. Nevertheless, there is room for improvements of these techniques with regard to sample volume, selectivity and sensitivity, sample preparation time and simplicity (eg potential utility to handle whole-blood samples). The present review purports to give a brief overview of current applications, advances, limitations and future prospective uses of sample preparation, radiometabolite analysis and plasma protein binding methods in conjunction with positron emission tomography studies.
•A method to determine plasma protein binding of PET radioligands was developed.•The method was based on high-performance frontal analysis (HPFA).•The method was simple and rapid considering the ...short half lives of radionuclides.•Good agreement with results from ultrafiltration method was achieved.
Positron emission tomography (PET) is an imaging technique based on the use of radioligands labeled with short lived radionuclides, such as 11C (t½=20.4min) and 18F (t½=109.8min), which as a consequence often requires rapid plasma protein binding analysis methods. In addition, PET radioligands can suffer from non-specific binding to the membrane when ultrafiltraion, which is the most commonly used method for measuring protein binding in PET, is employed. In this study a high-performance frontal analysis (HPFA) method based on incorporation of a gel filtration column (discovery® BIO GFC 100, 50mm×4.6mm, 5μm, 100Å) into a radio-LC system with phosphate buffered saline (PBS, pH 7.4) at a flow rate of 3ml/min as mobile phase was developed and investigated for four PET radioligands. The minimum injection volume (MIV) of plasma, which is a crucial factor in HPFA, was determined to be 200μl (human), 500μl (monkey), 700μl (human) and 1000μl (monkey) for these four radioligands. The MIV values increased as a higher fraction of the radioligand was present in the protein-free form. The protein binding results obtained were in good agreement with ultrafiltration and the method did not suffer from non-specific binding. The short analysis time (<12min) allowed multiple protein binding measurements during time course of a human 11CPBR28 PET study.
Background:
Positron emission tomography microdosing of radiolabeled drugs allows for noninvasive studies of organ exposure in vivo. The aim of the present study was to examine and compare the brain ...exposure of 12 commercially available CNS drugs and one non-CNS drug.
Methods:
The drugs were radiolabeled with 11C (t
1/2
= 20.4 minutes) and examined using a high resolution research tomograph. In cynomolgus monkeys, each drug was examined twice. In rhesus monkeys, a first positron emission tomography microdosing measurement was repeated after preadministration with unlabeled drug to examine potential dose-dependent effects on brain exposure. Partition coefficients between brain and plasma (K
P) were calculated by dividing the AUC0-90 min for brain with that for plasma or by a compartmental analysis (V
T). Unbound K
P (K
P u,u) was obtained by correction for the free fraction in brain and plasma.
Results:
After intravenous injection, the maximum radioactivity concentration (C
max, %ID) in brain ranged from 0.01% to 6.2%. For 10 of the 12 CNS drugs, C
max, %ID was >2%, indicating a preferential distribution to brain. A lower C
max, %ID was observed for morphine, sulpiride, and verapamil. K
P ranged from 0.002 (sulpiride) to 68 (sertraline) and 7 of 13 drugs had K
P u,u close to unity. For morphine, sulpiride, and verapamil, K
P u,u was <0.3, indicating impaired diffusion and/or active efflux. Brain exposure at microdosing agreed with pharmacological dosing conditions for the investigated drugs.
Conclusions:
This study represents the largest positron emission tomography study on brain exposure of commercially available CNS drugs in nonhuman primates and may guide interpretation of positron emission tomography microdosing data for novel drug candidates.
A general method is presented for the identification of radiometabolites in plasma of human and monkey subjects after administration of positron emission tomography (PET) radioligands. The ...radiometabolites are first produced in vitro, using liver microsomes, subsequently separated using fast radio-liquid chromatography (radio-LC), and individually collected and identified by ultra high-performance liquid chromatography/quadrupole-time of flight-mass spectrometry in MS and MS
E
mode. Fast radio-LC provided superior resolution compared to conventional radio-LC, resulting in separation of a greater number of metabolites. The radiometabolites produced in vivo are then compared to and identified based on the in vitro results. This approach was applied to three PET radioligands,
11
Cflumazenil,
18
FFE-PE2I, and
11
CPBR28, resulting in the identification of five, two, and one radiometabolites, respectively. This procedure can easily be adopted to identify the radiometabolites produced in vivo from a variety of PET radioligands.
A new method for the reduction of no‐carrier‐added 11Ccarbon dioxide into 11Ccarbon monoxide (11CCO) is described, in which the reductant (zinc) is supported on fused silica particles. Using this ...setup, which allows for a reduction temperature (485°C) well above the melting point for zinc (420°C), radiochemical yields of up to 96% (decay‐corrected) were obtained. A slight decrease in radiochemical yield was observed upon repeated 11CCO productions (93 ± 3%, n = 20). The methodology is convenient and efficient and provides a straightforward path to no‐carrier‐added production of 11CCO.
A new and convenient method for the efficient conversion of no‐carrier‐added 11Ccarbon dioxide into 11Ccarbon monoxide has been developed. The reduction is mediated by zinc supported by fused silica particles. This method is technically straightforward, provides near‐quantitative radiochemical yield, and represents a straightforward path to no‐carrier‐added 11Ccarbon monoxide.
Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation‐positive (EGFRm) non‐small cell lung cancer (NSCLC). Osimertinib is a third‐generation, ...irreversible, EGFR‐tyrosine kinase inhibitor that potently and selectively inhibits EGFR‐sensitizing and T790M resistance mutations with efficacy in EGFRm NSCLC including central nervous system (CNS) metastases. The open‐label phase I positron emission tomography (PET) and magnetic resonance imaging (MRI) study (ODIN‐BM) assessed 11Cosimertinib brain exposure and distribution in patients with EGFRm NSCLC and BMs. Three dynamic 90‐min 11Cosimertinib PET examinations were acquired together with metabolite‐corrected arterial plasma input functions at: baseline, after first oral osimertinib 80 mg dose, and after greater than or equal to 21 days of osimertinib 80 mg q.d. treatment. Contrast‐enhanced MRI was performed at screening and after 25–35 days of osimertinib 80 mg q.d.; treatment effect was assessed per CNS Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and per volumetric changes in total BM using a novel analysis approach. Four patients (aged 51–77 years) completed the study. At baseline, ~1.5% injected radioactivity reached the brain (IDmaxbrain) 22 min (median, Tmaxbrain) after injection. Total volume of distribution (VT) in whole brain was numerically higher compared with the BM regions. After a single oral osimertinib 80 mg dose, there was no consistent decrease in VT in whole brain or BMs. After greater than or equal to 21 days' daily treatment, VT in whole brain and BMs were numerically higher versus baseline. MRI revealed 56%–95% reduction in total BMs volume after 25–35 days of osimertinib 80 mg q.d. treatment. The 11Cosimertinib crossed the blood–brain and brain‐tumor barriers and had a high, homogeneous brain distribution in patients with EGFRm NSCLC and BMs.
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