No carrier added synthesis of O-(2′-[18F]fluoroethyl)-l-tyrosine via a novel type of chiral enantiomerically pure precursor, NiII complex of a (S)-tyrosine Schiff base
Graphical abstract
Introduction
Positron emission tomography (PET), based on the imaging of pharmaceuticals labeled with short-lived positron-emitting radionuclides, is a rapidly growing modality for the diagnosis and management of cancer.1 At present 2-[18F]-fluoro-2-deoxy-d-glucose ([18F]FDG) is the most widely used PET radiotracer for tumor imaging,1, 2 which exploits the abnormal glucose metabolism of malignant cells.3 Although [18F]FDG has been effective radiotracer for a variety of malignancies,1, 2 it has limited application in brain tumors imaging, because of high glucose uptake in a grey matter. [18F]FDG accumulation in inflamed tissues and granulation cells makes it difficult to differentiate malignant tumors from benign lesions as the main source of false-positive PET findings.4, 5 Labeled amino acids constitute an alternate class of PET tracers for indicating tumor activity by measuring trans-membrane transport rate, which is accelerated in malignant cells.6, 7, 8 They demonstrated a minimal uptake in the normal brain parenchyma and relatively low accumulation in inflamed tissues. Among amino acids radiotracers, l-[11C-methyl]methionine (l-[11C]MET) remains the most popular one, mainly due to the ease of its synthesis. However the short half-life of carbon-11 (t1/2 = 20.4 min) has a potential disadvantage of being used only in PET centers with an expensive in-house cyclotron. Fluorinated compounds labeled with longer-lived fluorine-18 (t1/2 = 109.8 min) have practical benefits, they can be transported to centers remote from production/cyclotron site.
Despite a variety of 18F-labeled amino acids ([18F]FAAs) have being suggested as tumor seeking agents for PET,7, 8 their clinical application has been hampered by difficult synthesis. Particularly difficult is nucleophilic synthesis of the [18F]FAAs with label introduced into the aromatic moiety. Such procedures involve several synthetic steps and are difficult to adapt for routine productions.9, 10, 11 Alternatively the introduction of 18F-label into the alkyl chain can be achieved via aliphatic nucleophilic substitution and allows to produce radiotracers in clinically relevant amounts. Of several structurally similar o-fluoroalkyl substituted tyrosines, O-(2′-[18F]fluoroethyl)-l-tyrosine ([18F]FET),12 O-(3-[18F]fluoropropyl)-l-tyrosine,13 and O-(2′-[18F]fluoromethyl)-l-tyrosine,14 [18F]FET has gained particular attention. An initial study demonstrated that an uptake of [18F]FET in brain tumors is similar to that of l-[11C]MET.15 [18F]FET is not metabolized and not incorporated into proteins, it is actively transported into tumor cells by specific amino acid transport system l and in part by Na+-dependent system B0+.16, 17 Further reports have shown high uptake of [18F]FET in cerebral18, 19, 20, 21 and peripheral tumors.22 In contrast to l-[11C]MET and [18F]FDG, [18F]FET exhibits negligible uptake in inflammatory tissues in animals model.23, 24 In the recent studies in humans the usefulness of [18F]FET as a molecular probe for the differentiation of tumor and inflammation has been confirmed.25
Growing interest to clinical application of [18F]FET has stimulated developments of new synthesis strategies that could be suitable for routine use. In the first published synthesis12 [18F]FET was prepared via alkylation of the di-potassium salt of l-tyrosine with [18F]fluoroethyltosylate. The process involved separation of the 18F-alkylating intermediate from starting tosyloxyethane by semi-preparative HPLC. This laborious procedure with double preparative HPLC steps was not easy adaptable to automation. Later the purification of [18F]fluoroethyltosylate on disposable SPE cartridges was reported,26 however this method was not ideal for automated productions due to multiplicity of purification steps using various solvents.
The synthesis of [18F]FET was substantially improved by the implementation of direct nucleophilic radiofluorination process on protected alkyl tyrosine derivative, O-(2-tosyloxyethyl)-N-trityl-l-tyrosine tert.-butylester (1, Fig. 1).27 Deprotection of amino and carboxy functions was carried out in solution of trifluoroacetic acid in dichloromethane. Enantiomerically pure [18F]FET was obtained in a radiochemical yield of 60% using remote-controlled synthesis module.28 However, the necessity to remove the solvent and an aggressive TFA by SPE technique preceding the final HPLC purification step resulted in a relatively long and complex radiochemistry sequence.
In the further studies similar precursor structure with different protecting groups, O-(2-tosyloxyethyl)-N-tert.-butyloxycarbonyl-l-tyrosine benzyl ester (2, Fig. 1), was suggested.29 It should be noted that the change-over of the protecting groups may lead to racemization of amino acid moiety within the course of 18F-fluorination reaction, performing under basic conditions.27 Unfortunately, the enantiomeric purity of [18F]FET obtained via 18F-nucleophilic fluorination of 2 was not reported.29
Based on our experience in asymmetric synthesis of amino acids,30, 31, 32, 33 we pursued a different approach to [18F]FET by elaborating a new leading structure of labeling precursor.34 The novel type of the precursor arose from NiII complex of a Schiff’s base of (S)-[N-2-(N′-benzylprolyl)amino]benzophenone (BPB) with alkylated (S)-tyrosine, Ni-(S)-BPB-(S)-Tyr-OCH2CH2X (3, Fig. 1); X = OTs (3a), OMs (3b), OTf (3c). The precursor has some advantages which include (a) simple preparation from commercial reagents; (b) stability under reaction basic conditions and retention of desired (S)-configuration of amino acid;30, 31 (c) one stage removal of the chiral auxiliary and simultaneous deprotection of amino and carboxy functions under mild conditions.
Herein, we describe the preparation of this novel type of precursor 3 and authentic FET. We also report one-pot two-steps radiosynthesis of [18F]FET via direct nucleophilic fluorination of 3 with no carrier added (n.c.a.) [18F]fluoride in the presence of two phase transfer catalysts, tetra butylammonium carbonate (TBAC) and Kryptofix 2.2.2. (K2.2.2.)/K2CO3 complex. Biological evaluation of [18F]FET obtained via new synthesis approach has been performed in experimental rat’s model of tumor and inflammation.
Section snippets
Chemistry
The synthesis of a novel chiral diastereoisomerically pure precursor for [18F]FET, a NiII complex of a Schiff’s base of (S)-[N-2-(N′-benzylprolyl)amino]benzophenone (BPB) with (S)-tyrosine, in which the OH-group of the tyrosine moiety was converted into OCH2CH2OTs derivative Ni-(S)-BPB-(S)-Tyr-OCH2CH2OTs (3a), is depicted in Scheme 1. At the first synthesis stage the Ni-(S)-BPB-(S)-Tyr complex (4) was easily prepared from a nickel nitrate salt, (S)-BPB and racemic tyrosine in the presence of
Conclusions
In conclusion, the nucleophilic substitution of the leaving group in the novel labeling precursor, NiII complex of a Schiff’s base of (S)-[N-2-(N′-benzylprolyl)amino]-benzophenone ((S)-BPB) with alkylated (S)-tyrosine, Ni-(S)-BPB-(S)-Tyr-OCH2CH2X (3a–c), is a feasible way to a fully automated production of [18F]FET, an important amino acid tracer for tumor diagnosis with PET. Based on the comparison within a series of labeling precursors 3a–c, the tosylate derivative 3a has appeared to be the
Materials and general procedures
All NMR spectra were recorded on a Bruker Avance 400 instrument (400.13 MHz for 1H, 100.16 MHz for 13C and 161 MHz for 19F) using CDCl3 as a solvent (unless indicated otherwise). Chemical shifts of peaks are presented in ppm (δ-scale with 0.00 ppm for TMS) with, using residual deuterated solvent signal as an internal standard. Optical rotations were measured with a Perkin-Elmer 241 polarimeter in a thermostated cell at 25 °C. All solvents were distilled prior to use. Melting points were determined
Acknowledgments
The authors thank the cyclotron engineers Mr. Alexandr Demianov and Mr. Vladimir Obolencev for performing the irradiations of the fluorine-18 target. This work was supported by Grant 2780 from the ISTC and a Grant 06-0308089-ofi from Russian Foundation of Basic Researches.
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