Enantiospecific synthesis of 2-[18F]fluoro-L-phenylalanine and 2-[18F]fluoro-L-tyrosine by isotopic exchange

2-[(18)F]Fluoro-L-phenylalanine and 2-[(18)F]fluoro-L-tyrosine have been developed as promising radiopharmaceuticals for molecular imaging using positron emission tomography (PET). However, the lack of a convenient radiosynthetic pathway has limited their practical use. In this work a new three-step nucleophilic synthesis of these compounds starting from [(18)F]fluoride is described. Corresponding precursors (1a and 1b) were (18)F-fluorinated by isotopic exchange, followed by the removal of an activating formyl group with Rh(PPh(3))(3)Cl and subsequent hydrolysis of protecting groups in acidic medium. All reactions were carried out using both conventional and microwave heating. Conventional heated reactions yielded the desired products 2-[(18)F]Fphe and 2-[(18)F]Ftyr in 43% and 49% whereas radiochemical yields of 34% and 43%, respectively, were obtained when they were heated by microwaves. Under optimized conditions the enantiomeric purity was ≥94% for both radiopharmaceuticals.     

1-[18F]Fluoroethyleneglycol-2-nitroimidazoles, a new class of potential hypoxia PET markers

Summary 1-[2-(2-Fluoroethoxy)ethyl]-2-1H-nitroimidazole (3a), 1-{2-[2-(2-fluoroethoxy)ethoxy]ethyl}-2-1H-nitroimidazole (3b) and 1-(2-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}ethyl)-2-1H-nitroimidazole (3c) were synthesized in a two step sequence.Coupling the ditosylate of di-, tri- or tetraethylene glycol with 2-nitroimidazole followed by fluoride substitution afforded the reference compounds in high yield and¹⁸F labeling gave the corresponding markers in 70-82% radiochemical yield.     

Synthesis and reactivity of [18F]-N-fluorobenzenesulfonimide

A novel [18F]NF reagent and two novel radiochemical transformations have been developed: [18F]NFSi has been prepared from sodium dibenzenesulfonimide and reacted in the presence of silyl enol ethers and allylsilanes to deliver labelled fluorinated ketones and allylic fluorides respectively; the radiosynthesis of the fluorinated A ring of vitamin D3 has also been completed with success.     

Positron-emitting N-[18F]fluoroalkyl and [18F]fluoropyrrolidinyl analogues of eticlopride as potential in vivo radioligands for dopamine D2 receptors.

N-Fluoroalkyl and 4-fluoropyrrolidinyl eticlopride analogues with high affinity toward central nervous system dopamine D2 receptors in vitro were labelled with positron emitting fluorine-18 (t1/2 = 110 min), and their in vivo biodistribution was investigated in rats. N-[18F]Fluoro-ethyl and -propyl eticlopride derivatives showed poor in vivo selectivity in the rat brain. On the other hand, 4-[18F]fluoropyrrolidinyl eticlopride exhibited almost constant and relatively high striatal concentration. The striatal/cerebellar radioactivity ratio, which corresponds to the ratio of a brain D2 receptor-rich to poor region, gradually increased to 5.2-6.4, 90 min after the injection. The striatal accumulation was selectively inhibited by pre-injection of haloperidol, a dopamine D2 antagonist, without affecting accumulation in other tissues. Thus, the selective striatal accumulation of 4-[18F]fluoropyrrolidinyl eticlopride in striatal tissue appears to be due to the specific binding to dopamine D2 receptors.     

Preparation of 18F labeled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine using indirect and direct labeling methods

Summary Shanghai 201800, P.R. China     

Synthesis and evaluation of N-(2-[18F]fluoro-4-nitrobenzoyl)glucosamine: a preliminary report

d-glucosamine at concentration of certain range could kill tumor cells without influencing normal cells. There are also some reports on the antitumor activity of d-glucosamine and its derivatives in murine models. It was therefore postulated that d-glucosamine might have the potential to invade tumor cells. We designed and radiosynthesized a glucosamine derivative, N-(2-[¹⁸F]fluoro-4-nitrobenzoyl)glucosamine ([¹⁸F]FNBG([¹⁸F]7)). Evaluations in vitro and in vivo were performed on tumor bearing mice. Excitingly, the radiochemical purity of [¹⁸F]FNBG([¹⁸F]7) was 99%, and besides the best radiochemical yield was up to 35%. The best T/Bl (Tumor/Blood) and T/M (Tumor/Muscle) ratios of [¹⁸F]FNBG([¹⁸F]7) were 4.40 and 4.84. Although [¹⁸F]FNBG([¹⁸F]7) deserved further studies, the results revealed it might become a potential PET imaging agent for detecting tumors.     

Radiochemical Synthesis of 4-[18F]FluorobenzylAzide and Its Conjugation with EGFR-Specific Aptamers

Central nervous system tumors related to gliomas are of neuroectodermal origin and cover about 30% of all primary brain tumors. Glioma is not susceptible to any therapy and surgical attack remains one of the main approaches to its treatment. Preoperative tumor imaging methods, such as positron emission tomography (PET), are currently used to distinguish malignant tissue to increase the accuracy of glioma removal. However, PET is lacking a specific visualization of cells possessing certain molecular markers. Here, we report an application of aptamers to enhancing specificity in imaging tumor cells bearing the epidermal growth factor receptor (EGFR). Glioblastoma is characterized by increased EGFR expression, as well as mutations of this receptor associated with active division, migration, and adhesion of tumor cells. Since 2021, EGFR has been included into the WHO classification of gliomas as a molecular genetic marker. To obtain conjugates of aptamers GR20 and GOL1-specific to EGFR, a 4-[¹⁸F]fluorobenzylazide radiotracer was used as a synthon. For the production of the synthon, a method of automatic synthesis on an Eckert & Ziegler research module was adapted and modified using spirocyclic iodonium ylide as a precursor. Conjugation of 4-[¹⁸F]fluorobenzylazide and alkyne-modified aptamers was carried out using Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) with/without the TBTA ligand. As a result, it was possible to obtain ¹⁸F-labelled conjugates with 97% radiochemical purity for [¹⁸F]FB-GR20 and 98% for [¹⁸F]FB-GOL1. The obtained conjugates can be used for further studies in PET analysis on model animals with grafted glioblastoma.     

(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 1-amino-3-[(dihydroxyboryl)methyl]- cyclobutanecarboxylic acid as a potential therapy agent

A novel boronated aminocyclobutanecarboxylic acid (1) was synthesized for potential use in boron neutron capture therapy. Starting from the readily available 3-(bromomethyl)cyclobutanone ketal (4), several synthetic routes to 1 were evaluated. After several unsuccessful attempts with traditional synthetic methods, a novel synthetic strategy to generate the new boronated cyclic amino acid was developed. The tolerance of the hydantoin group to the selenoxide elimination reaction conditions in the preparation of alkenyl compound 7 proved to be the key step in the new strategy.     

Synthesis of no-carrier-added 4-[18F]fluorophenol from 4-benzyloxyphenyl-(2-thienyl)iodonium bromide

4-[(18)F]Fluorophenol is a versatile synthon for the synthesis of more complex radiopharmaceuticals bearing a 4-[(18)F]fluorophenoxy moiety. In order to prepare 4-[(18)F]fluorophenol in no-carrier-added (n.c.a.) form only a nucleophilic labelling method starting from [(18)F]fluoride is suitable. In this paper a new, two step radiosynthesis starting from 4-benzyloxyphenyl-(2-thienyl)iodonium bromide and [(18)F]fluoride with subsequent deprotection is described, yielding n.c.a. [(18)F]fluorophenol in 34 to 36% radiochemical yield.     

The synthesis of methano-bridged bisdehydro [18]-, -[20]-, -[22]-, and -[24] annulenes

Title annulenes were synthesized by Wittig reaction of cyclohepta-1,3,5-triene-1,6-dialdehyde or its vinylogous dialdehydes with 5-methylpenten-2-yn-4-yltriphenylphosphonium bromide, followed by intramolecular oxidative couplings of the resulting acyclic compounds, and they proved to be diatropic or paratropic, corresponding to the number of peripheral π-electrons.     

Synthesis of 6-[18F]fluoroveratraldehyde by nucleophilic halogen exchange at electron-rich precursors

Summary Fluorodehalogenation reactions were used to prepare 6-[¹⁸F]fluoroveratraldehyde. The synthesis of 6-[¹⁸F]fluoroveratraldehyde is the first step in the multi-step synthesis of the clinically important tracer 6-[¹⁸F]fluoro-L-dopa. In the literature yields ranging from 20-50% are reported when using nitro and trimethylammoniumtriflate precursors. However, no data exist concerning the use of different leaving groups such as halogens. Therefore, 6-bromo, 6-chloro and 6-fluoroveratraldehyde were tested in the nucleophilic aromatic substitution by [¹⁸F]fluoride. In DMF, 6-[¹⁸F]fluoroveratraldehyde was obtained with radiochemical yields of (57±1.0)% and (66±3.6)% in 20 minutes at 160 °C using 50 mg/ml bromo and chloro precursor, respectively. The fluoro precursor gave a radiochemical yield of (87±0.8)% at 140 °C. Temperature, solvent and concentration strongly affected the ¹⁸F-labeling. Among the halogens the ability as a leaving group was F>>Cl>Br. The halogenated veratraldehydes provide a good alternative for the synthesis of ca and nca 6-[¹⁸F]fluoroveratraldehyde, as the first step of the synthesis for [¹⁸F]FDOPA since they are inexpensive, commercially available, stable, sustain hard conditions in the labeling step, and give yields better or equal to other precursors previously reported.     

Synthesis of [2-C]-oleanolic acid and [2-C]-myricerone

Synthetic way for ¹³C-labeled oleanolic acid 1 and myricerone 2 has been developed, starting from the parent 1 and 2. The procedure involves ring opening and closure of the A rings of these oleanane triterpenes. ¹³C was introduced into the 2-position by ¹³C-MeLi as an isotope source. Chelation controlled addition of methyllithium to -hydoxypentanone 11 is a common crucial step for labeling of 1 and 2, and judicious choice of protecting groups is essential for 2.     

Radiosynthesis of [18F]-5-[2-(2-chlorophenoxy)phenyl]-1,3,4-oxadiazole-2-yl-4-fluorobenzoate: A labeled ligand for benzodiazepine receptors

5-[2-(2-Chlorophenoxy)phenyl]-1,3,4-oxadiazole-2-yl-4-fluorobenzoate 6a, the non-classic benzodiazepine ligand, has been shown to elicit a significant anticonvulsant activity against pentylenetetrazole-induced convulsion. In order to perform biological studies, we decided to prepare the [¹⁸F]-labeled compound. This compound was prepared in no-carrier-added (n.c.a) form from 5-[2-(2-chlorophenoxy)phenyl]-1,3,4-oxadiazole-2-yl-4-N,N,N-trimethylanilinium triflate 5 in one step at 125 °C in Kryptofix 2.2.2/[¹⁸F] and DMSO as the solvent followed by column chromatography. The synthesis took 20 minutes with an overall radiochemical yield of 70-75% (EOS) and a specific activity about 74 GBq/mmole and chemical-radiochemical purity more than 95%. This revised version was published online in July 2006 with corrections to the Cover Date.     

The synthesis of 1-[2-(dimethylamino)ethyl]-7,12-dihydro-3H-[2]-benzoxepino[4,3-e]indole : A potential antidepressant agent

The structures of doxepin and serotonin were overlayed using molecular graphics and 1 - [2-(dimethylamino)ethyl] - 7, 12 - dihydro - 3H - [2] - benzoxepino[4,3-e]indole(1) was proposed as a potential antidepressant agent. This paper deals with the synthesis of the title compound. Key steps in the synthesis include a regioselective electrophilic substitution at C-4 of ethyl 5-hydroxy-1-indolecarboxylate (4) and subsequent modification to 7,12-dihydro-3H-[2]-benzoxepino[4,3-e]indole(12). Standard procedures were then used to construct the dimethylaminoethyl side chain to yeild the title compound (1).     

Synthetic and structural studies of [6]-, [7]- and [10]metacyclophanes

A new preparative sequence from 2,3-polymethylene-2-cyclopentenone 5 to 2,6-polymethylenebromobenzenes 3 (n = 6, 7, 10) and 2,6-polymethylenephenyllithiums 6 has been found. The reaction of 6 with various electrophiles produces a number of new compounds to disclose the unique reactivity of the aryl C-Li moiety surrounded by the polymethylene chain. Photolysis of 3a and 3b provides transannular products 8, 10 and 11, all arising from the proximity between the aromatic bromine and the aliphatic hydrogen intraannularly opposed to be removed as HBr. Spectrometric study gives quantitative data of the dependence of the molecular geometry upon the chain length and the aromatic substituents. The energy barriers ΔG_c^≠ of the conformational flipping are 17·4 kcal/mol (T_c 76·5°) for [6]metacyclophane (7a), 11·5 kcal/mol (T_c ?28°) for [7]metacyclophane (7b), ·8 kcal/mol for [10]metacyclophane (7c). The lower-energy process of the aliphatic chain in [6]metacyclophane derivatives is the pseudorotation with substituent-dependent barrier ΔG_c^≠ 11·1 kcal/mol (T_c ?31·5°) for 7a, 12·4 kcal/mol (T_c ?4·5°) for 3a and 12·7 kcal/mol (T_c 1·0°) for 12a. The rather large rotational barrier is attributed to the compressed structure of each system. The benzene ring distortion of the cyclophanes is deduced from the bathochromic shift of the B-band and the diamagnetic shift of the benzene proton signals in the PMR.     

Synthesis and labeling of 5'-O-(4,4'-dimethoxytrityl)-2,3'-anhydr othymidine for [18F]FLT preparation

For in vivo measurement of DNA synthesis in the patient"s tumour 3"-[¹⁸F]fluoro-3"-deoxythymidine (FLT) has been shown to be very promising. As a new labeling precursor 5"-O-(4,4"-dimethoxytrityl)-2,3"-anhydrothymidine (DMTThy) was chosen and an organic synthesis was developed including NMR and MS data for characterisation. The ¹⁸F-labeling of DMTThy can be performed within 30 minutes in radiochemical yields of almost 20% when using polar solvents such as DMF or DMSO and a temperature of 160 °C. Hydrolysis is completed with 1N HCl at 50 °C within 10 minutes without losses.