Synthesis of 2-(1,1-dicyanopropen-2-yl)-6-(2-[18F]-fluoroethyl)-methylamino-naphthalene ([18F]FDDNP)
Introduction
2-(1,1-Dicyanopropen-2-yl)-6-(2-[18F]-fluoroethyl)-methylamino-naphthalene ([18F]FDDNP) allows for in vivo visualization of fibrillary amyloid depositions and neurofibrillary tangles in the brain. As such, it could be an important tool in the early diagnosis and study of Alzheimer's disease (Agdeppa et al., 2001; Cai et al., 2007; Cohen, 2007; Nordberg, 2004; Shoghi-Jadid et al., 2002; Small et al., 2006; Wu et al., 2005).
The synthesis of [18F]FDDNP was first described by Barrio et al., 1999, Barrio et al., 2001. This method, however, resulted in a relatively low yield and required the use of normal phase preparative HPLC purification. The latter purification step is more complicated than the use of a reverse phase approach. Recently, Liu et al. (2007) reported an improved synthesis method for [18F]FDDNP with the application of reverse phase preparative HPLC purification. In addition, the stability of the [18F]FDDNP was investigated. The formation of an observed side product, the oxidized [18F]FDDNP analogue 1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethan-1-one ([18F]FENE), at aqueous basic conditions could be avoided by quenching the reaction mixture with diluted HCl. Unfortunately, stability of the resulting product was monitored only in a pure ethanolic solution, but in our lab it was observed that the product, dissolved in an isotonic water solution was not as stable as the product only in ethanol.
The purpose of the present study was to apply the latter method for synthesising [18F]FDDNP using a different reverse phase preparative HPLC purification method, and to explore the radiochemical stability of the formulated product. An important secondary objective was to exclude the intermediate purification of the reaction mixture as reported by Liu et al. (2007), in order to establish a more convenient synthesis procedure.
Section snippets
Materials and methods
Acetonitrile, Kryptofix 222 and potassium carbonate were obtained from Merck, other chemicals were obtained from Aldrich. All chemicals were used as received.
The starting material, 2-(1,1-dicyanopropen-2-yl)-6-(2-tosyloxyoethyl)-methylamino-naphthalene was obtained from ABX.
HPLC for semi-preparative separation was performed with a Jasco PU1587 pump, an in-line Jasco UV1575 UV detector (wavelength 254 nm), a flow through radioactivity detector with GM tube (home-made) and Jasco-Borwin software
Synthesis of [18F]-FDDNP
Fluorination was performed as depicted in Scheme 1.
Different reaction times, temperatures and solvents were investigated. Results are given in Table 1. Optimum reaction conditions were found to be 15 min at 100 °C in acetonitrile.
Semi-preparative HPLC purification
Subsequently, the reaction mixture was diluted with HPLC eluent and subjected to semi-preparative HPLC purification. In order to find an optimum purification method, several semi-prep systems were investigated: (1) a spherimage 250×16 mm with MeCN/H2O/AcOH 60/40/0.1 4
Conclusion
A fully automated, GMP compliant, reproducible procedure for the synthesis of [18F]FDDNP was developed. This synthesis was performed without any intermediate purification of the reaction mixture, making the production of [18F]FDDNP more convenient.
The [18F]FDDNP was found to be unstable, probably due to radiolysis in aqueous solutions, since the addition of ascorbic acid prevented this decomposition.
Quantitative, selective binding of the formulated product to the sterilizing filter was
Acknowledgement
The authors wish to thank P.J. van Leuffen and personnel of the BV Cyclotron VU for providing 18F. The FP6 network of excellence DiMI (LSH-2003-1.2.2.-2) is acknowledged for a contribution to this work.
References (13)
- et al.
Residual solvent analysis by gas chromatography in radiopharmaceutical formulations containing up to 12% of ethanol
Nucl. Med. Biol.
(2006) PET imaging of amyloid in Alzheimer's disease
Lancet Neurol.
(2004)- et al.
Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease
Am. J. Geriatr. Psychiatry
(2002) - et al.
The effectiveness of various scavengers on the γ-irradiated, methanolic solution of medazepam
Int. J. Pharm.
(1990) - et al.
Amyloid imaging: from benchtop to bedside
Curr. Top. Dev. Biol.
(2005) - et al.
Binding charcteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for β-amyloid plaques in Alzheimer's disease
J. Neurosci.
(2001)
Cited by (12)
Preclinical studies of potential amyloid binding PET/SPECT ligands in Alzheimer's disease
2012, Nuclear Medicine and BiologyCitation Excerpt :The decay-corrected radiochemical yields were 25% and 30%, respectively (Scheme 4). The synthesis of [18F]FDDNP was carried out by aliphatic nucleophilic fluorination of the corresponding N-ethyl tosylate or mesylate of amino naphthalene (Scheme 5) and published by two groups in 2007 [35] and 2008 [36], respectively. Both groups reported similar radiochemical yield of around 40%; however, the latter group explored a different HPLC method for purification and the stability of the formulated final product.
Studies into radiolytic decomposition of fluorine-18 labeled radiopharmaceuticals for positron emission tomography
2009, Applied Radiation and IsotopesPeripheral metabolism of [<sup>18</sup>F]FDDNP and cerebral uptake of its labelled metabolites
2008, Nuclear Medicine and BiologyPositron emission tomography radioligands for in vivo imaging of Aβ plaques
2013, Journal of Labelled Compounds and Radiopharmaceuticals