Preparation,Optimisation, and In Vitro Evaluation of [18F]AlF-NOTA-Pamidronic Acid for Bone Imaging PET

[¹⁸F]sodium fluoride ([¹⁸F]NaF) is recognised to be superior to [⁹⁹mTc]-methyl diphosphate ([^99mTc]Tc-MDP) and 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) in bone imaging. However, there is concern that [¹⁸F]NaF uptake is not cancer-specific, leading to a higher number of false-positive interpretations. Therefore, in this work, [¹⁸F]AlF-NOTA-pamidronic acid was prepared, optimised, and tested for its in vitro uptake. NOTA-pamidronic acid was prepared by an N-Hydroxysuccinimide (NHS) ester strategy and validated by liquid chromatography-mass spectrometry analysis (LC-MS/MS). Radiolabeling of [¹⁸F]AlF-NOTA-pamidronic acid was optimised, and it was ensured that all quality control analysis requirements for the radiopharmaceuticals were met prior to the in vitro cell uptake studies. NOTA-pamidronic acid was successfully prepared and radiolabeled with ¹⁸F. The radiolabel was prepared in a 1:1 molar ratio of aluminium chloride (AlCl₃) to NOTA-pamidronic acid and heated at 100 °C for 15 min in the presence of 50% ethanol (v/v), which proved to be optimal. The preliminary in vitro results of the binding of the hydroxyapatite showed that [¹⁸F]AlF-NOTA-pamidronic acid was as sensitive as [¹⁸F]sodium fluoride ([¹⁸F]NaF). Normal human osteoblast cell lines (hFOB 1.19) and human osteosarcoma cell lines (Saos-2) were used for the in vitro cellular uptake studies. It was found that [¹⁸F]NaF was higher in both cell lines, but [¹⁸F]AlF-NOTA-pamidronic acid showed promising cellular uptake in Saos-2. The preliminary results suggest that further preclinical studies of [¹⁸F]AlF-NOTA-pamidronic acid are needed before it is transferred to clinical research.     

[F]Fluoromethyl iodide ([F]FCH2I): preparation and reactions with phenol, thiophenol, amide and amine functional groups

In this study, we report the synthesis and reactivity of [¹⁸F]fluoromethyl iodide ([¹⁸F]FCH₂I) with various nucleophilic substrates and the stabilities of [¹⁸F]fluoromethylated compounds. [¹⁸F]FCH₂I was prepared by reacting diiodomethane (CH₂I₂) with [¹⁸F]KF, and purified by distillation in radiochemical yields of 14-31% (n = 25). [¹⁸F]FCH₂I was stable in organic solvents commonly used for labeling and aqueous solution with pH 1-7, but was unstable in basic solutions. [¹⁸F]FCH₂I displayed a high reactivity with various nucleophilic substrates such as phenol, thiophenol, amide and amine. The [¹⁸F]fluoromethylated compounds synthesized by the reactions of phenol, thiophenol and tertiary amine with [¹⁸F]FCH₂I were stable for purification, formulation and storage. In contrast, the [¹⁸F]fluoromethylated compounds synthesized by the reactions of primary or secondary amines, and amide with [¹⁸F]FCH₂I were too unstable to be detected or purified from the reaction mixtures. Defluorination of these [¹⁸F]fluoromethyl compounds was a main decomposition route.     

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]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)     

[18F]Nifene PET/CT Imaging in Mice: Improved Methods and Preliminary Studies of α4β2* Nicotinic Acetylcholinergic Receptors in Transgenic A53T Mouse Model of α-Synucleinopathy and Post-Mortem Human Parkinson’s Disease

We report [¹⁸F]nifene binding to α4β2* nicotinic acetylcholinergic receptors (nAChRs) in Parkinson’s disease (PD). The study used transgenic Hualpha-Syn(A53T) PD mouse model of α-synucleinopathy for PET/CT studies in vivo and autoradiography in vitro. Additionally, postmortem human PD brain sections comprising of anterior cingulate were used in vitro to assess translation to human studies. Because the small size of mice brain poses challenges for PET imaging, improved methods for radiosynthesis of [¹⁸F]nifene and simplified PET/CT procedures in mice were developed by comparing intravenous (IV) and intraperitoneal (IP) administered [¹⁸F]nifene. An optimal PET/CT imaging time of 30–60 min post injection of [¹⁸F]nifene was established to provide thalamus to cerebellum ratio of 2.5 (with IV) and 2 (with IP). Transgenic Hualpha-Syn(A53T) mice brain slices exhibited 20–35% decrease while in vivo a 20–30% decrease of [¹⁸F]nifene was observed. Lewy bodies and α-synuclein aggregates were confirmed in human PD brain sections which lowered the [¹⁸F]nifene binding by more than 50% in anterior cingulate. Thus [¹⁸F]nifene offers a valuable tool for PET imaging studies of PD.     

Automated synthesis of symmetric integrin αvβ3-targeted radiotracer [18F]FP-PEG3-β-Glu-RGD2

A automated synthesis of symmetric integrin α_vβ₃-targeted radiotracer [¹⁸F]FP-PEG₃-β-Glu-RGD₂ was carried out by multi-step procedure on the modified PET-MF-2V-IT-I synthesizer. Firstly, the prosthetic group of 4-nitrophenyl 2-[¹⁸F]fluoropropionate ([¹⁸F]NFP) was automated synthesized by a convenient three-step, one-pot procedure. Secondly, [¹⁸F]FP-PEG₃-β-Glu-RGD₂ was synthesized by coupling [¹⁸F]NFP with the symmetric RGD-peptide (PEG₃-β-Glu-RGD₂) and purified by a solid-phase extraction cartridge. The radiochemical yields of [¹⁸F]NFP were 35 ± 5 % (n = 10, decay-corrected) based on [¹⁸F]fluoride in 80 min. [¹⁸F]FP-PEG₃-β-Glu-RGD₂ was obtained with yield 40 ± 10 % (n = 5, decay-corrected) from [¹⁸F]NFP within 20 min. The radiochemical purity of [¹⁸F]FP-PEG₃-β-Glu-RGD₂ was greater than 98 %.     

(S)-2-((S)-2-(4-(3-[18F]fluoropropyl)benzamido)-3-phenylpropanamido)pentanedioic acid labeled with 18F

As degradation product of Antineoplaston A10 in vivo, phenylacetyl glutamine showed antitumor activities. According to literatures, we designed and radiosynthesized a phenylacetyl glutamine derivative, which was achieved under a mild reaction condition. Evaluations in vitro and in vivo were performed on tumor bearing mice. Excitingly, the radiochemical purity of (S)-2-((S)-2-(4-(3-fluoropropyl)benzamido)-3-phenylpropanamido)pentanedioic acid ([¹⁸F]FBPPA) was 98%, and besides the best radiochemical yield was up to 46%. T/Bl (Tumor/Blood) and T/M (Tumor/Muscle) ratios of [¹⁸F]FBPPA at 60 min post injection were 2.33 and 3.51. Meanwhile, it showed satisfied stability in vitro and in vivo, compared with 2-[¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG). Although [¹⁸F]FBPPA deserved further studies to make optimizations on its structure, the results revealed it might become a potential PET imaging agent for detecting tumors.     

Synthesis of para‐[18F]Fluorofenbufen Octylamide for PET Imaging of Brain Tumors

Glioma is a brain tumor associated with a poor therapeutic outcome with an average life expectancy of 14 months. Cyclooxygenase‐2 (COX‐2) expression is associated with the progression of the tumor and is considered a therapeutic target of chemo agents. Para‐[¹⁸F]Fluorofenbufen octylamide ([¹⁸F]FFOA) was obtained with the radiochemical yield of 16% and specific activity of 4 GBq/μmol, and the IC₅₀ values of COX‐1 and COX‐2 were 26.5 and 32.7 μM, respectively. The stability of cold FFOA in plasma was significantly improved with a half‐life of 30 min, and the uptake ratio of [¹⁸F]FFOA in rats with brain tumor was 1.5 as determined from accumulation of 3.9% injection dose (ID/g) in the brain tumor and 2.5% ID/g in the brain. [¹⁸F]FFOA with COX‐2 micromolar affinity can be used to differentiate between brain tumor and normal region.     

Efficient alkali iodide promoted F-fluoroethylations with 2-[F]fluoroethyl tosylate and 1-bromo-2-[F]fluoroethane

Radiochemical ¹⁸F-fluorination yields of several compounds using the secondary labelling precursors 2-[¹⁸F]fluoroethyl tosylate ([¹⁸F]FETos) and 1-bromo-2-[¹⁸F]fluoroethane ([¹⁸F]BFE) could be considerably enhanced by the addition of an alkali iodide. The radiochemical yield of [¹⁸F]fluoroethyl choline for example could be doubled with [¹⁸F]BFE and increased from 13% to ≈80% with [¹⁸F]FETos. By addition of alkali iodide to the precursor, the ¹⁸F-fluoroethylation yields of established radiopharmaceuticals, especially in the case of automated syntheses, could be significantly increased without major changes of the reaction conditions.     

Radiosynthesis of 10-(2-[18F]fluoroethoxy)-20(S)-camptothecin as a potential positron emission tomography tracer for the imaging of topoisomerase I in cancers

The preparation of 10-(2-[¹⁸F]fluoroethoxy)-20(S)-camptothecin, a potential positron emission tomography tracer for the imaging of topoisomerase I in cancers, is described. 10-(2-[¹⁸F]Fluoroethoxy)-20(S)-camptothecin was synthesized by the [¹⁸F]fluoroalkylation of the corresponding hydroxy precursor molecule with 2-[¹⁸F]fluoroethyl bromide ([¹⁸F]FEtBr) in dimethylsulfoxide (DMSO) at 55 °C for 20 min; this was followed by purification using high performance liquid chromatography (HPLC) with a total preparation time of 60 min. The overall radiochemical yield was approximately 5.4–12 % (uncorrected), and the radiochemical purity was above 96 %.     

Rapid Detection of the Residual Kryptofix 2.2.2 Levels in [18F]-Labeled Radiopharmaceuticals by Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry

A fast and sensitive ultra-performance liquid chromatography-tandem mass spectrometric (UPLC/MS/MS) method was developed and validated for determination of the residual levels of Kryptofix 2.2.2 (K222) in [¹⁸F]-labeled radiopharmaceuticals. The analytical time was only 3 min, and the injection volume was 5 μL. An electrospray ionization source was used in the positive mode (ESI⁺) for UPLC/MS/MS. The analytical measurements were performed in the multiple reaction monitoring (MRM) mode. The calibration curve at the spiked concentrations of 2–500 ng/mL for K222 showed good linearity. The intra- and inter-day precisions were not more than 5%. The accuracy satisfied the requirement of quality control analysis, the recoveries were found to be 80–120%. This method was successfully applied to detect the residue of K222 in [¹⁸F]-fluorodeoxyglucose [(¹⁸F)FDG], [¹⁸F]-fluoromisonizole[(¹⁸F)FMISO], 3′-deoxy-3′-[¹⁸F]-fluorothymidine [(¹⁸F)FLT], and two new [¹⁸F]-labeled radiopharmaceuticals 4-[-(2-[¹⁸F]fluoroethoxy) methyl]-1-[2-(2-methyl-5-nitro-1H- imidazol-1-yl) ethyl]-1H-1,2,3-triazole (named as ¹⁸F-BNU-1) and 4-[-(2-[¹⁸F] fluoroethoxy) methyl]-1-[2-(2-nitro-1H-imidazol-1-yl) ethyl]-1H-1,2,3-triazole (named as ¹⁸F-BNU-2) produced in our lab.     

Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-O-(2-Fluoroethyl) Moiety and the Potential of Their 18F-Labeled Derivatives for Neuroinflammation Imaging

Neolignans honokiol and 4′-O-methylhonokiol (MH) and their derivatives have pronounced anti-inflammatory activity, as evidenced by numerous pharmacological studies. Literature data suggested that cyclooxygenase type 2 (COX-2) may be a target for these compounds in vitro and in vivo. Recent studies of [¹¹C]MPbP (4′-[¹¹C]methoxy-5-propyl-1,1′-biphenyl-2-ol) biodistribution in LPS (lipopolysaccharide)-treated rats have confirmed the high potential of MH derivatives for imaging neuroinflammation. Here, we report the synthesis of four structural analogs of honokiol, of which 4′-(2-fluoroethoxy)-2-hydroxy-5-propyl-1, 1′-biphenyl (F-IV) was selected for labeling with fluorine-18 (T_1/2 = 109.8 min) due to its high anti-inflammatory activity confirmed by enzyme immunoassays (EIA) and neuromorphological studies. The high inhibitory potency of F-IV to COX-2 and its moderate lipophilicity and chemical stability are favorable factors for the preliminary evaluation of the radioligand [¹⁸F]F-IV in a rodent model of neuroinflammation. [¹⁸F]F-IV was prepared with good radiochemical yield and high molar activity and radiochemical purity by ¹⁸F-fluoroethylation of the precursor with Boc-protecting group (15) with [¹⁸F]2-fluoro-1-bromoethane ([¹⁸F]FEB). Ex vivo biodistribution studies revealed a small to moderate increase in radioligand uptake in the brain and peripheral organs of LPS-induced rats compared to control animals. Pretreatment with celecoxib resulted in significant blocking of radioactivity uptake in the brain (pons and medulla), heart, lungs, and kidneys, indicating that [¹⁸F]F-IV is likely to specifically bind to COX-2 in a rat model of neuroinflammation. However, in comparison with [¹¹C]MPbP, the new radioligand showed decreased brain uptake in LPS rats and high retention in the blood pool, which apparently could be explained by its high plasma protein binding. We believe that the structure of [¹⁸F]F-IV can be optimized by replacing the substituents in the biphenyl core to eliminate these disadvantages and develop new radioligands for imaging activated microglia.     

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.     

PET Imaging of Fructose Metabolism in a Rodent Model of Neuroinflammation with 6-[18F]fluoro-6-deoxy-D-fructose

Fluorine-18 labeled 6-fluoro-6-deoxy-D-fructose (6-[¹⁸F]FDF) targets the fructose-preferred facilitative hexose transporter GLUT5, which is expressed predominantly in brain microglia and activated in response to inflammatory stimuli. We hypothesize that 6-[¹⁸F]FDF will specifically image microglia following neuroinflammatory insult. 6-[¹⁸F]FDF and, for comparison, [¹⁸F]FDG were evaluated in unilateral intra-striatal lipopolysaccharide (LPS)-injected male and female rats (50 µg/animal) by longitudinal dynamic PET imaging in vivo. In LPS-injected rats, increased accumulation of 6-[¹⁸F]FDF was observed at 48 h post-LPS injection, with plateaued uptake (60–120 min) that was significantly higher in the ipsilateral vs. contralateral striatum (0.985 ± 0.047 and 0.819 ± 0.033 SUV, respectively; p = 0.002, n = 4M/3F). The ipsilateral–contralateral difference in striatal 6-[¹⁸F]FDF uptake expressed as binding potential (BP_SRTM) peaked at 48 h (0.19 ± 0.11) and was significantly decreased at one and two weeks. In contrast, increased [¹⁸F]FDG uptake in the ipsilateral striatum was highest at one week post-LPS injection (BP_SRTM = 0.25 ± 0.06, n = 4M). Iba-1 and GFAP immunohistochemistry confirmed LPS-induced activation of microglia and astrocytes, respectively, in ipsilateral striatum. This proof-of-concept study revealed an early response of 6-[¹⁸F]FDF to neuroinflammatory stimuli in rat brain. 6-[¹⁸F]FDF represents a potential PET radiotracer for imaging microglial GLUT5 density in brain with applications in neuroinflammatory and neurodegenerative diseases.     

Association between monthly-reported rhinitis by children from basic schools and monthly-averaged air pollutants,at Lisbon (Portugal)

3-(4-[¹⁸F]fluorobenzyl)-8-hydroxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one ([¹⁸F]FHTP) was in vitro and in vivo evaluated as a putative dopamine D₄ receptor radioligand. Its inhibition constant (K _i ) for cloned human dopamine D_4.2 receptor was determined to be 2.9 nM and it displayed a 2000-fold D₄-selectivity over the D_2long subtype. Its partition coefficient (logP) was measured to be 1.11. Biodistribution, blocking distribution and metabolism studies in rats demonstrated that the specific distribution of [¹⁸F]FHTP in brain regions, suggesting that [¹⁸F]FHTP may be a suitable PET imaging agent for in vivo studies of the dopamine D₄ receptor.     

Clinical Relevance of [18F]Florbetaben and [18F]FDG PET/CT Imaging on the Management of Patients with Dementia

PET of β-Amyloid plaques (Aβ) using [¹⁸F]florbetaben ([¹⁸F]FBB) and [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) increasingly aid clinicians in early diagnosis of dementia, including Alzheimer’s disease (AD), frontotemporal disease, dementia with Lewy bodies, and vascular dementia. The aim of this retrospective analysis was to evaluate clinical relevance of [¹⁸F]FBB, [¹⁸F]FDG PET and complimentary CSF measurements in patients with suspected dementia. In this study, 40 patients with clinically suspected or history of dementia underwent (1) measurement of Aβ peptides, total tau, and p-tau protein levels in the cerebrospinal fluid (CSF) compared with healthy controls (HC); (2) clinical and neuropsychological assessment, which included Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological assessment battery (CERAD-NAB); (3) [¹⁸F]FBB and [¹⁸F]FDG PET imaging within an average of 3 weeks. The subjects were within 15 days stratified using PET, CSF measurements as HC, mild cognitive impaired (MCI) and dementia including Alzheimer´s disease. The predictive dementia-related cognitive decline values were supporting the measurements. PET images were evaluated visually and quantitatively using standard uptake value ratios (SUVR). Twenty-one (52.5%) subjects were amyloid-positive (Aβ+), with a median neocortical SUVR of 1.80 for AD versus 1.20 relative to the respective 19 (47.5 %) amyloid-negative (Aβ-) subjects. Moreover, the [¹⁸F]FDG and [¹⁸F]FBB confirmed within a sub-group of 10 patients a good complimentary role by correlation between amyloid pathology and brain glucose metabolism in 8 out of 10 subjects. The results suggest the clinical relevance for [¹⁸F]FBB combined with [¹⁸F]FDG PET retention and CFS measurements serving the management of our patients with dementia. Therefore, [¹⁸F]FBB combined with [¹⁸F]FDG PET is a helpful tool for differential diagnosis, and supports the patients’ management as well as treatment.     

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.     

Synthesis and characterization of the two enantiomers of a chiral sigma-1 receptor radioligand: (S)-(+)- and (R)-(-)-[18F]FBFP

Racemic [¹⁸F]FBFP ([¹⁸F]1) proved to be a potent σ₁ receptor radiotracer with superior imaging properties. The pure enantiomers of unlabeled compounds (S)- and (R)-1 and the corresponding iodonium ylide precursors were synthesized and characterized. The two enantiomers (S)-1 and (R)-1 exhibited comparable high affinity for σ₁ receptors and selectivity over σ₂ receptors. The Ca²⁺ fluorescence assay indicated that (R)-1 behaved as an antagonist and (S)-1 as an agonist for σ₁ receptors. The ¹⁸F-labeled enantiomers (S)- and (R)-[¹⁸F]1 were obtained in >99% enantiomeric purity from the corresponding enantiopure iodonium ylide precursors with radiochemical yield of 24.4% ± 2.6% and molar activity of 86–214 GBq/µmol. In ICR mice both (S)- and (R)-[¹⁸F]1 displayed comparable high brain uptake, brain-to-blood ratio, in vivo stability and binding specificity in the brain and peripheral organs. In micro-positron emission tomography (PET) imaging studies in rats, (S)-[¹⁸F]1 exhibited faster clearance from the brain than (R)-[¹⁸F]1, indicating different brain kinetics of the two enantiomers. Both (S)- and (R)-[¹⁸F]1 warrant further evaluation in primates to translate a single enantiomer with more suitable kinetics for imaging the σ₁ receptors in humans.     

Efficient synthesis of (2S)-tert-butyl 2-(2-bromopropanamido)-5-oxo-5-(tritylamino)pentanoate as a precursor of PET radiotracer [18F]FPGLN

This study describes a convenient protocol for the synthesis of (2S)-tert-butyl 2-(2-bromopropanamido)-5-oxo-5-(tritylamino)pentanoate, which can serve as an appropriate precursor of (2S)-5-amino-2-(2-[¹⁸F]fluoropropanamido)-5-oxopentanoic acid (N-(2-[¹⁸F]fluoropropionyl)-L-glutamine, [¹⁸F]FPGLN) for tumor positron emission tomography imaging. Five-step synthesis starting from L-glutamine provided the desired precursor with high yields. In addition, a simple method for the preparation of [¹⁸F]FPGLN from this easily available precursor was developed using a two-step ¹⁸F-labeling strategy.     

Methods for the synthesis of fluorine-18-labeled aromatic amino acids,radiotracers for positron emission tomography (PET)

Potential of electrophilic and nucleophilic methods of radiofluorination in the synthesis of fluorine-18-labeled fluorinated amino acid analogs, radiotracers for positron emission tomography (PET), is considered. The synthesis of 6-L-[¹⁸F]FDOPA ((S)-2-amino-3-(6-[¹⁸F]fluoro-3,4-dihydroxyphenyl)propionic acid) was used as an example to discuss new elaborations in this field directed on both the improvement of already existing methods and the development of fundamentally new approaches to the introduction of a fluorine-18 label into the nonactivated aromatic ring of amino acids using nucleophilic methods.