Radiofluorination of 2-fluoropyridines by isotopic exchange with [<Superscript>18</Superscript>F]fluoride

In homoaromatic systems, isotopic exchange (¹⁸F/¹⁹F) was previously (J Label Compd Radiopharm 18(12):1721–1730 [2], J Chem Soc Perkin Trans 1(3):295–298 [3]) proven to be advantageous, yet in general specific activity is thought to be low. For heteroaromatic systems, in particular, very few examples are published regarding the ¹⁸F-labelling of 2-substituted pyridines (J Label Compd Radiopharm 42:975–985 [9]). Therefore, in 2-fluoropyridines, we decided to study the ¹⁸F labelling by isotopic exchange (¹⁸F/¹⁹F). The radiochemical yield for 2-fluoropyridine was 90 ± 2%. Even if 2-fluoropyridine was substituted by an electron-donating group such as a methyl or a methoxy group, radiochemical yields were 80 ± 1 and 78 ± 1%, respectively. Although in benzenes, these substituents are known to decrease nucleophilic substitutions by ¹⁸F-Fluoride significantly. Moreover, by choosing appropriate concentrations of 2-fluoropyridines, reasonably high specific activities up to 10 GBq/μmol were obtained.     

Radiosynthesis and preliminary biological evaluation of the 2-[<Superscript>18</Superscript>F]fluoropropionic acid enantiomers for tumor PET imaging

The aim of this study was to synthesize the optically pure [¹⁸F]FPA, and to investigate the diagnostic value of different isomers. Semi-automated radiosynthesis of R-[¹⁸F]FPA or S-[¹⁸F]FPA was respectively from the chiral precursor (S)- or (R)-ethyl 2-(((trifluoromethyl)sulfonyl)oxy)propanoate via a two-step reaction and performed on the commercial FDG synthesizer. The improved radiochemical yields of R-[¹⁸F]FPA and S-[¹⁸F]FPA were 30–40% (decay-uncorrected, n = 10) in 35 min. There was no significant difference on the biodistribution of two enantiomers in normal mice (P > 0.05), but positron emission tomography imaging demonstrated that R-[¹⁸F]FPA was more suitable for PC3 tumor imaging than S-[¹⁸F]FPA and [¹⁸F]FDG.     

Nucleophilic aromatic substitution by [<Superscript>18</Superscript>F]fluoride at substituted 2-nitropyridines

For the radiofluorination of benzenes and benzene derivatives, the electrophilic reaction with [¹⁸F]F₂ is a very common route. Yet, aromatic nucleophilic substitution (S_NAr) by n.c.a [¹⁸F]fluoride, which can be produced efficiently in high amounts, has been considered to be very desirable. However, to facilitate ¹⁸F-labelling via S_NAr at an electron rich aromatic system, an appropriate leaving group must be present together with an auxiliary group in ortho or para position to the leaving group. An interesting alternative for the auxiliary group is the heteroatom of a heteroaromatic system, for which pyridine is a leading example. Dolci et al. (J Label Compd Radiopharm 42:975–985, 1999) have evaluated the scope of the nucleophilic aromatic fluorination of 2-substituted pyridine rings using the activated K [¹⁸F]F-K₂₂₂ complex. As methyl and methoxy groups are known to enhance the electron density of an aromatic system by the +I and the +M effect, respectively, S_NAr is unlikely to occur. Until now, the effect of these substituents has not been studied towards the ¹⁸F-radiofluorination of substituted 2-nitropyridines by use of [¹⁸F]fluoride. Therefore, we have investigated the effect of methoxy and methyl groups in 2-nitropyridines. The results showed that 3-methoxy-2-nitropyridine and 3-methyl-2-nitropyridine can efficiently be substituted by [¹⁸F]fluoride with high RCY’s (70–89%) in short reaction times (1–30 min) at a reaction temperature of 140 °C. Moreover, 3-methoxy-6-methyl-2-[¹⁸F]fluoropyridine was obtained from the corresponding nitro-precursor in a high yield of 81 ± 1% after 30 min at 140 °C. In case of 2-nitropyridines data indicates the effect of methyl and methoxy groups on S_NAr to be of minor importance.     

Broad Scope and High-Yield Access to Unsymmetrical Acyclic [11C]Ureas for Biomedical Imaging from [11C]Carbonyl Difluoride

Effective methods are needed for labelling acyclic ureas with carbon-11 (t_1/2=20.4 min) as potential radiotracers for biomedical imaging with positron emission tomography (PET). Herein, we describe the rapid and high-yield syntheses of unsymmetrical acyclic [¹¹C]ureas under mild conditions (room temperature and within 7 min) using no-carrier-added [¹¹C]carbonyl difluoride with aliphatic and aryl amines. This methodology is compatible with diverse functionality (e. g., hydroxy, carboxyl, amino, amido, or pyridyl) in the substrate amines. The labelling process proceeds through putative [¹¹C]carbamoyl fluorides and for primary amines through isolable [¹¹C]isocyanate intermediates. Unsymmetrical [¹¹C]ureas are produced with negligible amounts of unwanted symmetrical [¹¹C]urea byproducts. Moreover, the overall labelling method tolerates trace water and the generally moderate to excellent yields show good reproducibility. [¹¹C]Carbonyl difluoride shows exceptional promise for application to the synthesis of acyclic [¹¹C]ureas as new radiotracers for biomedical imaging with PET.     

One-step conjugation of glycylglycine with [<Superscript>18</Superscript>F]FDG and a pilot PET imaging study

This study describes a single step conjugation of Glycylglycine (GlyGly) which is a small peptide, with [¹⁸F]FDG via oxime formation. Amiooxy-functionalization of GlyGly (AO-GlyGly) was accomplished through the reaction of Boc-aminooxy succinimide ester. Conjugation reaction was performed at 100 °C for 30 min in a vial containing AO-GlyGly and [¹⁸F]FDG solution. The radiolabeled product ([¹⁸F]FDG-GlyGly) was obtained with 98.65?±?0.35% yield without any purification step which makes this method more attractive for ¹⁸F radiolabeling. The present study is concluded with an in vivo pilot animal PET study to assess biodistribution and kinetics of chemoselectively [¹⁸F]FDG tagged GlyGly in vivo.     

Autoradiolysis of the 2-deoxy-2-[<Superscript>18</Superscript>F]fluoro-D-glucose radiopharmaceutical

Summary To control virtually the toxic compounds and to improve quality control of the solution of 2-deoxy-2-[¹⁸F]fluoro-d-glucose (2-[¹⁸F]FDG), the products of its autoradiolysis were analyzed by high-performance liquid chromatography with electrospray mass spectrometric and radiometric detectors (HPLC/MS/RAD), thin layer chromatography on TLC silica plate and HPTLC on amino modified silica plate. Except Kryptofix^™ 2.2.2, glucose and fluoride anion, no by-products and impurities were observed by LC/MS analysis of fresh 2-[¹⁸F]FDG samples. The analysis performed in the time interval of 6 to 48 hours after the end of 2-[¹⁸F]FDG synthesis indicated that the activity of the autoradiolysis products separated by HPLC did not exceed 1.3%. As the main autoradiolysis products of 3.3 ^. 10^-5 to 4.4 ^. 10^-5M 2-[¹⁸F]FDG solution of original specific activity 0.5-1.5 GBq ^. cm^-3 were established: arabinose - 2.8 μM (G= 0.07/100 eV), gluconic and glucuronic acids 1.8-0.5 μM (G =0.01-0.05/100 eV), arabinose and araburonic acids occurred under 0.5 μM concentration at residual glucose contents about 0.14 mM. Radiation chemical yields of active products were calculated from molar activity of 2-[¹⁸F]FDG and the percentage of their activity: 0.5% radiochemical yield of 2-[¹⁸F]fluoroglucuronic acid corresponds to the G = 0.004/100 eV and 0.3% yield of 2-[¹⁸F]fluorogluconic acid issues G = 0.003/100 eV.     

Synthesis of <Emphasis Type="Italic">O</Emphasis>-[2-[<Superscript>18</Superscript>F]fluoro-3-(2-nitro-1<Emphasis Type="Italic">H</Emphasis>-imidazole-1-yl)propyl]tyrosine ([<Superscript>18</Superscript>F]FNT]) as a new class of tracer for imaging hypoxia

For detection of hypoxic tumor tissue, all radiotracers synthesized until now, are based on the concept that cellular uptake is being controlled by diffusion. As a new approach, we chose the concept to have the tracer hypothetically transported into the cells by well known carrier systems like the amino acid transporters. For this purpose, radiosynthesis of O-[2-[¹⁸F]fluoro-3-(2-nitro-1H-imidazole-1yl)propyl]tyrosine ([¹⁸F]FNT]) was carried out from methyl 2-(benzyloxycarbonyl)-3-(4-3-(2-nitro-1H-imidazol-1-yl)-2-(tosyloxy)propoxy) phenyl)propanoate via no-carrier-added nucleophilic aliphatic substitution. After labelling, 81 ± 0.9% of labelled intermediate i.e. methyl 2-(benzyloxycarbonyl)-3-(4-(2-[¹⁸F]fluoro-3-(2-nitro-1H-imidazole-1-yl)propoxy) phenyl)propanoate was obtained at 140 °C. At the end of radiosynthesis, [¹⁸F]FNT was obtained in an overall radiochemical yield of 40 ± 0.9% (not decay corrected) within 90 min in a radiochemical purity of >98% in a formulation ready for application in the clinical studies for PET imaging of hypoxia.     

Preparation of [<Superscript>66</Superscript>Ga]bleomycin complex as a possible PET radiopharmaceutical

Summary Gallium-66 (T_1/2 = 9.49 h) is an interesting radionuclide that has potential use for positron emission tomography (PET) imaging of biological processes in intermediate to slow target tissue uptake. ⁶⁶Ga was produced in the NRCAM cyclotron as a result of 15 MeV proton bombardment of ⁶⁶Zn with current intensity of 180 μA (yield 11.2 mCi/μAh). Bleomycin (BLM) was labeled with [⁶⁶Ga]GaCl₃     

New technique to trace [<Superscript>15</Superscript>O]water uptake in a living plant with an imaging plate and a BGO detector system

Summary We present a new trial to measure real time water movement in a living plant using the positron emitting radionuclide, ¹⁵O. ¹⁵O was prepared by ¹⁴N(d,n)¹⁵O reaction and 10 ml of ¹⁵O labeled water (2 GBq) was supplied from the root of a soybean plant. To detect activity, an imaging plate (IP) as well as a BGO detector system were used. Since the half-life of ¹⁵O is extremely short, (T_1/2= 122 s), water uptake measurement was performed only for 20 minutes. In order to get [¹⁵O]waterimage, an IP was exposed to the plant for 1 minute for two times. Since the exposure to an IP requires dark condition, a BGO detector system was developed to measure [¹⁵O]waterunder light condition. A couple of BGO probes was set at the lowest stem and the gamma-rays (0.511 MeV) emitted from the radionuclide were measured through coincidence counting and compared with the radioactivity measured from an IP image. Using this system, we have found that the water uptake activity of the plant was drastically reduced under high humidity (99%) and dark condition.     

A new technique for labeling of [11C]-choline, a positron-emitting tracer for tumor imaging

Summary [¹¹C]-choline has been reported as a potential tracer for imaging a variety of human tumors with positron emission tomography (PET). A new labeling technique for [¹¹C]-choline was established depending on parameters optimized, such as reaction time, volume, temperature, and the quantity of DMAE.The synthesis yield was improved from 82.0% to 96.5% (EOB), while the consumption of DMAE precursor decreased from 60 to 2 mg. Absolute yield of [¹¹C]-choline was 2500 MBq for a 10-minute irradiation at15mA, and a total synthesis time of less than 8 minutes from [¹¹C]-CH₃I to [¹¹C]-choline.     

Metabolite analysis of [<Superscript>18</Superscript>F]Florbetaben (BAY 94-9172) in human subjects: a substudy within a proof of mechanism clinical trial

[¹⁸F]Florbetaben ([¹⁸F]BAY 94-9172) is a promising β-amyloid (Aβ) targeted PET-tracer currently in late stage clinical development. [¹⁸F]Florbetaben can assist in the more accurate diagnosis of Alzheimer’s Disease (AD) by non-invasive, in vivo detection of Aβ in the brain. To determine the arterial input function of the PET tracer—as part of a proof of mechanism (PoM) study—arterial samples were drawn from all subjects at predefined time points post injection (p.i.), and the proportion of unchanged tracer [¹⁸F]Florbetaben was determined by HPLC analysis. Plasma metabolite profiles were investigated following intravenous administration of 300 MBq (±60 MBq) of [¹⁸F]Florbetaben to both, patients with AD and healthy controls (HCs), and various methods for processing the blood samples were evaluated. Addition of acetonitrile to plasma samples (obtained from whole blood by centrifugation) and precipitation of proteins resulted in a recovery of more than 90% of the initial radioactivity in the supernatants. High Performance Liquid Chromatography using a polymer-based column (PRP-1) in conjunction with gradient elution was found to be a suitable method of metabolite analysis of [¹⁸F]Florbetaben. HPLC analyses indicated that [¹⁸F]Florbetaben is rapidly metabolized in vivo with an estimated initial half-life of about 6 min. A polar metabolite fraction, consisting presumably of more than one component, and (to a smaller extent) of the demethylated derivative of [¹⁸F]Florbetaben were time-dependently detected in plasma.     

[11C]-labeling of some caffeine derivatives for mapping adenosine A2a receptors by PET technique

[¹¹C]-labeled form of ten A_2a adenosine receptor specific 8-styryl-7-methyl-xanthine derivatives ([¹¹C]-caffeines) were synthesised by N-methylation of the corresponding 8-styryl-xanthine derivatives using [¹¹C]-methyl iodide in optimized reaction conditions. The results show that the [¹¹C]-methylations take place with excellent radiochemical yields (35–93%), and can be utilised easily in online preparations. These labeled ligands may facilitate the positron emission tomographic (PET) investigation of adenosine A_2a receptors.     

Fully automated radiosynthesis of [<Superscript>18</Superscript>F]Fluoromisonidazole with single neutral alumina column purification: optimization of reaction parameters

1-H-1-(3-[¹⁸F]fluoro-2-hydroxypropyl)-2-nitroimidazole ([¹⁸F]FMISO), is the most used hypoxia-imaging agent in oncology and we have recently reported a fully automated procedure for its synthesis using the Nuclear Interface FDG module and a single neutral alumina column for purification. Using 1-(2′-nitro-1′-imidazolyl)-2-O-tetra-hydropyranyl-3-O-toluenesulfonylpropanediol (NITTP) as the precursor, we have investigated the yield of [¹⁸F]FMISO using different reaction times, temperatures, and the amount of precursor. The overall yield was 48.4 ± 1.2% (n = 3), (without decay correction) obtained using 10 mg NITTP with the radio-fluorination carried out at 145 °C for 3 min followed by acid hydrolysis for 3 min at 125 °C in a total synthesis time of 32 ± 1 min. Increasing the precursor amount to 25 mg did not improve the overall yield under identical reaction conditions, with the decay uncorrected yield being 46.8 ± 1.6% (n = 3), but rather made the production less economical. It was also observed that the yield increased linearly with the amount of NITTP used, from 2.5 to 10 mg and plateaued from 10 to 25 mg. Radio-fluorination efficiency at four different conditions was also compared. It was also observed by radio thin layer chromatography (radio-TLC) that the duration of radio-fluorination of NITTP, not the radio-fluorination temperature favoured the formation of labeled thermally degraded product, but the single neutral alumina column purification was sufficient enough to obtain [¹⁸F]FMISO devoid of any radiochemical as well as cold impurities.     

Effective Preparation of [18F]Flumazenil Using Copper-Mediated Late-Stage Radiofluorination of a Stannyl Precursor

(1) Background: [¹⁸F]Flumazenil 1 ([¹⁸F]FMZ) is an established positron emission tomography (PET) radiotracer for the imaging of the gamma-aminobutyric acid (GABA) receptor subtype, GABA_A in the brain. The production of [¹⁸F]FMZ 1 for its clinical use has proven to be challenging, requiring harsh radiochemical conditions, while affording low radiochemical yields. Fully characterized, new methods for the improved production of [¹⁸F]FMZ 1 are needed. (2) Methods: We investigate the use of late-stage copper-mediated radiofluorination of aryl stannanes to improve the production of [¹⁸F]FMZ 1 that is suitable for clinical use. Mass spectrometry was used to identify the chemical by-products that were produced under the reaction conditions. (3) Results: The radiosynthesis of [¹⁸F]FMZ 1 was fully automated using the iPhase FlexLab radiochemistry module, affording a 22.2 ± 2.7% (n = 5) decay-corrected yield after 80 min. [¹⁸F]FMZ 1 was obtained with a high radiochemical purity (>98%) and molar activity (247.9 ± 25.9 GBq/µmol). (4) Conclusions: The copper-mediated radiofluorination of the stannyl precursor is an effective strategy for the production of clinically suitable [¹⁸F]FMZ 1.     

Analysis of Pros and Cons in Using [68Ga]Ga-PSMA-11 and [18F]PSMA-1007: Production,Costs, and PET/CT Applications in Patients with Prostate Cancer

The aim of this work is to compare [⁶⁸Ga]Ga-PSMA-11 and [¹⁸F]PSMA-1007 PET/CT as imaging agents in patients with prostate cancer (PCa). Comparisons were made by evaluating times and costs of the radiolabeling process, imaging features including pharmacokinetics, and impact on patient management. The analysis of advantages and drawbacks of both radioligands might help to make a better choice based on firm data. For [⁶⁸Ga]Ga-PSMA-11, the radiochemical yield (RCY) using a low starting activity (L, average activity of 596.55 ± 37.97 MBq) was of 80.98 ± 0.05%, while using a high one (H, average activity of 1436.27 ± 68.68 MBq), the RCY was 71.48 ± 0.04%. Thus, increased starting activities of [⁶⁸Ga]-chloride negatively influenced the RCY. A similar scenario occurred for [¹⁸F]PSMA-1007. The rate of detection of PCa lesions by Positron Emission Tomography/Computed Tomography (PET/CT) was similar for both radioligands, while their distribution in normal organs significantly differed. Furthermore, similar patterns of biodistribution were found among [¹⁸F]PSMA-1007, [⁶⁸Ga]Ga-PSMA-11, and [¹⁷⁷Lu]Lu-PSMA-617, the most used agent for RLT. Moreover, the analysis of economical aspects for each single batch of production corrected for the number of allowed PET/CT examinations suggested major advantages of [¹⁸F]PSMA-1007 compared with [⁶⁸Ga]Ga-PSMA-11. Data from this study should support the proper choice in the selection of the PSMA PET radioligand to use on the basis of the cases to study.     

[18F]Ethenesulfonyl Fluoride as a Practical Radiofluoride Relay Reagent

Fluorine-18 is the most utilized radioisotope in positron emission tomography (PET), but the wide application of fluorine-18 radiopharmaceuticals is hindered by its challenging labelling conditions. As such, many potentially important radiotracers remain underutilized. Herein, we describe the use of [¹⁸F]ethenesulfonyl fluoride (ESF) as a novel radiofluoride relay reagent that allows radiofluorination reactions to be performed in minimally equipped satellite nuclear medicine centres. [¹⁸F]ESF has a simple and reliable production route and can be stored on inert cartridges. The cartridges can then be shipped remotely and the trapped [¹⁸F]ESF can be liberated by simple solvent elution. We have tested 18 radiolabelling precursors, inclusive of model and clinically used structures, and most precursors have demonstrated comparable radiofluorination efficiencies to those obtained using a conventionally dried [¹⁸F]fluoride source.     

Preparation of N-[11C]methyl-2,5-dimethoxy-4-bromo-amphetamine

For in vivo receptor studies N-[¹¹C]methyl-2,5-dimethoxy-4-bromo-amphetamine, [¹¹C]MDOB, was synthesized by the reaction of [¹¹C]CH₃I with DOB in acetonitrile. The labelling yield was determined in dependence on amount of precursor, time and temperature of the methylation reaction. During 10 to 15 minutes 60% to 70% of [¹¹C]MDOB has been obtained at 110°C.     

Synthesis of <Emphasis Type="Italic">O</Emphasis>-(2-[<Superscript>18</Superscript>F]fluoroethyl)-<Emphasis Type="Italic">L</Emphasis>-tyrosine and its biological evaluation in B16 melanoma-bearing mice as PET tracer for tumor imaging

O-(2-[¹⁸F]fluoroethyl)-L-tyrosine ([¹⁸F]FET), a fluorine-18 labeled analogue of tyrosine, has been synthesized and biologically evaluated in tumor-bearing mice. The whole synthesis procedure is completed within 50 min. The radiochemical yield is about 40% (no decay corrected) and radiochemical purity more than 97% after simplified solid phase extraction. [¹⁸F]FET shows rapid, high uptake and long retention in the tumor as well as low uptake in the brain. The ratios of tumor-to-muscle (T/M) and tumor-to-blood (T/B) of [¹⁸F]FET are similar to those of [¹⁸F]FDG, but the ratios of tumor-to-brain (T/Br) are 2–3 times higher than that of [¹⁸F]FDG. Autoradiography of [¹⁸F]FET demonstrates a remarkable accumulation in melanoma with high contrast. It appears to be a probable competitive candidate for melanoma imaging with PET. Supported by the Knowledge Innovation Project of Chinese Academy of Sciences (No. KJCX1-SW-08) and the National Natural Science Foundation of China (Grant No. 30371634)     

Production and quality control of [<Superscript>166</Superscript>Ho]-DOTA-bevacizumab for therapeutic applications

Antiangiogenic monoclonal antibodies in combination with therapeutic radionuclides are potential targeted therapy agents in cancer. In this study, bevacizumab was successively labeled with [¹⁶⁶Ho]HoCl₃ after conjugation with DOTA-NHS-ester with a radiochemical purity of higher than 95% (RTLC). The conjugates were purified by molecular filtration, the average number of DOTA conjugated per mAb was calculated and total concentration was determined by spectrophotometric method and the average chelate to antibody ratio (c/a) for the conjugate used in this study was 5.8:1 and protein integrity experiments (SDS-PAGE). The biodistribution studies in wild-type rats demonstrate a similar pattern to the other radiolabeled anti-vascular endothelial growth factor A (VEGF-A) immunoconjugates. ¹⁶⁶Ho-DOTA-bevacizumab is a potential compound for therapy/imaging of VEGF-A expression in oncology.     

Preparation of N-[11C]methyl-2,5-dimethoxy-4-methylamphetamine

In order to evaluate the neurobiological mechanism causing the psychogenic effects of N-methyl-2,5-dimethoxy-4-methylamphetamine (MDOM), the¹¹C labelled analogue was prepared for application in in vivo PET studies by the reaction of 2,5-dimethoxy-4-methylamphetamine (DOM) with [¹¹C]CH₃I. The radiochemical yield was determined in dependence on time, temperature, solvent and amount of substrate. The best conditions for fast labelling reactions with¹¹C on a preparative scale were found to be a reaction time of 10 miutes at 110°C using 1 mg DOM in acetonitrile thus obtaining radiochemical yields of 80% (based on produced [¹¹C]CH₃I).