A facile automated synthesis of N‐succinimidyl 4‐[18F]fluorobenzoate ([18F]SFB) for 18F‐labeled cell‐penetrating peptide as PET tracer

A fully automated synthesis of N‐succinimidyl 4‐[¹⁸F]fluorobenzoate ([¹⁸F]SFB) was carried out by a convenient three‐step, one‐pot procedure on the modified TRACERlab FX_FN synthesizer, including [¹⁸F]fluorination of ethyl 4‐(trimethylammonium triflate)benzoate as the precursor, saponification of the ethyl 4‐[¹⁸F]fluorobenzoate with aqueous tetrapropylammonium hydroxide instead of sodium hydroxide, and conversion of 4‐[¹⁸F]fluorobenzoate salt ([¹⁸F]FBA) to [¹⁸F]SFB treated with N,N,N′,N′‐tetramethyl‐O‐(N‐succinimidyl)uranium tetrafluoroborate (TSTU). The purified [¹⁸F]SFB was used for the labeling of Tat membrane‐penetrating peptide (containing the Arg‐Lys‐Lys‐Arg‐Arg‐Arg‐Arg‐Arg‐Arg‐Arg‐Arg‐Pro‐Leu‐Gly‐Leu‐Ala‐Gly‐Glu‐Glu‐Glu‐Glu‐Glu‐Glu‐Glu sequence, [¹⁸F]CPP) through radiofluorination of lysine amino groups. The uncorrected radiochemical yields of [¹⁸F]SFB were as high as 25–35% (based on [¹⁸F]fluoride) (n=10) with a synthesis time of～40 min. [¹⁸F]CPP was produced in an uncorrected radiochemical yields of 10–20% (n=5) within 30 min (based on [¹⁸F]SFB). The radiochemical purities of [¹⁸F]SFB and [¹⁸F]CPP were greater than 95%. Copyright © 2010 John Wiley & Sons, Ltd.     

Automated synthesis and purification of [18F]fluoro‐[di‐deutero]methyl tosylate

Automated synthetic procedures of [¹⁸F]fluoro‐[di‐deutero]methyl tosylate on a GE TRACERlab FX F‐N module and a non‐commercial synthesis module have been developed. The syntheses included azeotropic drying of the [¹⁸F]fluoride, nucleophilic ¹⁸F‐fluorination of bis(tosyloxy)‐[di‐deutero]methane, HPLC purification and subsequent formulation of the synthesized [¹⁸F]fluoro‐[di‐deutero]methyl tosylate (d₂‐[¹⁸F]FMT) in organic solvents. Automation shortened the total synthesis time to 50 min, resulting in an average radiochemical yield of about 50% and high radiochemical purity (>98%). The possible application of this procedure to commercially available synthesis modules might be of significance for the production of deuterated ¹⁸F‐fluoromethylated imaging probes in the future. Copyright © 2013 John Wiley & Sons, Ltd.     

Fully automated synthesis and purification of 4‐(2′‐methoxyphenyl)‐1‐[2′‐(N‐2″‐pyridinyl)‐p‐[18F]fluorobenzamido]ethylpiperazine

We have developed an efficient synthesis method for the rapid and high‐yield automated synthesis of 4‐(2′‐methoxyphenyl)‐1‐[2′‐(N‐2″‐pyridinyl)‐p‐[¹⁸F]fluorobenzamido]ethylpiperazine (p‐[¹⁸F]MPPF). No‐carrier‐added [¹⁸F]F^? was trapped on a small QMA cartridge and eluted with 70% MeCN(aq) (0.4 mL) containing Kryptofix 222 (2.3 mg) and K₂CO₃ (0.7 mg). The nucleophilic [¹⁸F]fluorination was performed with 3 mg of the nitro‐precursor in DMSO (0.4 mL) at 190 °C for 20 min, followed by the preparative HPLC purification (column: COSMOSIL Cholester, Nacalai Tesque, Kyoto, Japan; mobile phase: MeCN/25 mm AcONH₄/AcOH = 200/300/0.15; flow rate: 6.0 mL/min) to afford p‐[¹⁸F]MPPF (retention time = 9.5 min). p‐[¹⁸F]MPPF was obtained automatically with a radiochemical yield of 38.6 ± 5.0% (decay corrected, n = 5), a specific activity of 214.3 ± 21.1 GBq/µmol, and a radiochemical purity of >99% within a total synthesis time of about 55 min. Copyright © 2012 John Wiley & Sons, Ltd.     

Automated production at the curie level of no‐carrier‐added 6‐[18F]fluoro‐ l‐dopa and 2‐[18F]fluoro‐ l‐tyrosine on a FASTlab synthesizer

An efficient, fully automated, enantioselective multi‐step synthesis of no‐carrier‐added (nca) 6‐[¹⁸F]fluoro‐L‐dopa ([¹⁸F]FDOPA) and 2‐[¹⁸F]fluoro‐L‐tyrosine ([¹⁸F]FTYR) on a GE FASTlab synthesizer in conjunction with an additional high‐ performance liquid chromatography (HPLC) purification has been developed. A PTC (phase‐transfer catalyst) strategy was used to synthesize these two important radiopharmaceuticals. According to recent chemistry improvements, automation of the whole process was implemented in a commercially available GE FASTlab module, with slight hardware modification using single use cassettes and stand‐alone HPLC. [¹⁸F]FDOPA and [¹⁸F]FTYR were produced in 36.3 ± 3.0 % (n = 8) and 50.5 ± 2.7 % (n = 10) FASTlab radiochemical yield (decay corrected). The automated radiosynthesis on the FASTlab module requires about 52 min. Total synthesis time including HPLC purification and formulation was about 62 min. Enantiomeric excesses for these two aromatic amino acids were always >95 %, and the specific activity of was >740 GBq/µmol. This automated synthesis provides high amount of [¹⁸F]FDOPA and [¹⁸F]FTYR (>37 GBq end of synthesis (EOS)). The process, fully adaptable for reliable production across multiple PET sites, could be readily implemented into a clinical good manufacturing process (GMP) environment.     

Synthesis and stability of S‐(2‐[18F]fluoroethyl)‐L‐homocysteine for potential tumour imaging

The F‐18 labelled methionine derivative S‐(2‐[¹⁸F]fluoroethyl)‐L‐homocysteine ([¹⁸F]FEHCys) was prepared by a one‐pot two‐step synthesis via the protected S‐(2‐bromoethyl)‐L‐homocysteine 1 and S‐(2‐chloroethyl)‐L‐homocysteine 2 precursors. The bromoethyl derivative 1 gave higher radiochemical yields (40% at 5 min) at 100°C compared with the chloro‐analogue (22% at 100°C in 30 min). However, [¹⁸F]FEHCys was found to be unstable in aqueous systems being transformed to the corresponding hydroxyl derivative within 20 min. Copyright © 2008 John Wiley & Sons, Ltd.     

Radiochemical synthesis of 2′‐[18F]‐labelled and 3′‐[18F]‐labelled nucleosides for positron emission tomography imaging

This review article considers 2′‐labelled and 3′‐labelled nucleosides, which are of great importance as positron emission tomography (PET) probes in clinical diagnostics and PET research. Although the radiochemical preparation of several [¹⁸F]‐labelled nucleosides such as [¹⁸F]fluorothymidine or [¹⁸F](fluoroarabinofuranosyl)cytosine has been accomplished within the last two decades, a number of potentially interesting nucleoside‐based biomarkers are not yet available for automated good manufacturing practice production due to the lack of fast and efficient synthetic methods for late‐stage [¹⁸F]‐introduction. In order to meet recent demands for new PET‐based biomarkers in various clinical applications, appropriate precursors that can easily be fluorinated and deprotected need to be developed.     

Radiosynthesis of 3‐(2′‐[18F]fluoro)‐flumazenil ([18F]FFMZ)

Recently, two fluorine‐18 labelled derivatives of flumazenil were described: 5‐(2′‐[¹⁸F]fluoroethyl)‐5‐desmethylflumazenil (ethyl 8‐fluoro‐5‐[¹⁸F]fluoroethyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a] [1,4]diazepine‐3‐carboxylate; [¹⁸F]FEFMZ) and 3‐(2′‐[¹⁸F]fluoro)‐flumazenil (2′‐[¹⁸F]fluoroethyl 8‐fluoro‐5‐methyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a]‐[1,4]diazepine‐3‐carbo‐ xylate; [¹⁸F]FFMZ). Since the biodistribution data of the latter were superior to those of the former we developed a synthetic approach for [¹⁸F]FFMZ starting from a commercially available precursor, thereby obviating the need to prepare a precursor by ourselves. The following two‐step procedure was developed: First, [¹⁸F]fluoride was reacted with 2‐bromoethyl triflate using the kryptofix/acetonitrile method to yield 2‐bromo‐[¹⁸F]fluoroethane ([¹⁸F]BFE). In the second step, distilled [¹⁸F]BFE was reacted with the tetrabutylammonium salt of 3‐desethylflumazenil (8‐fluoro‐5‐methyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a] [1,4]diazepine‐3‐carboxylic acid) to yield [¹⁸F]FFMZ. The synthesis of [¹⁸F]FFMZ allows for the production of up to 7 GBq of this PET‐tracer, enough to serve several patients. [¹⁸F]FFMZ synthesis was completed in less than 80 min and the radiochemical purity exceeded 98%. Copyright © 2003 John Wiley & Sons, Ltd.     

Automated commercial synthesis system for preparation of O‐(2‐[18F]fluoroethyl)‐L‐tyrosine by direct nucleophilic displacement on a resin column

A slightly modified automated commercial synthesis system for preparation of O‐(2‐[¹⁸F]fluoroethyl)‐l‐tyrosine (FET), an amino acid tracer for tumor imaging with positron emission tomography, is described. Direct nucleophilic fluorination of [¹⁸F]fluoride with 1,2‐di(4‐methylphenylsulfonyloxy)ethane on a quaternary 4‐(4‐methylpiperidinyl)‐pyridinium functionalized polystyrene anion exchange resin gave 1‐[¹⁸F]‐2‐(4‐methylphenylsulfonyloxy)ethane, then [¹⁸F]fluoroalkylation of l‐tyrosine yielded FET. The overall radiochemical yield with no decay correction was about 8–10%, the whole synthesis time was about 52 min, and the radiochemical purity was above 95%. Copyright © 2003 John Wiley & Sons, Ltd.     

Alternative solvents for electrophilic synthesis of 6‐[18F]fluoro‐L‐DOPA

Owing to the ozone layer‐depleting properties of chlorofluorocarbon compounds, alternative solvents for electrophilic fluorination reactions are desirable. Chloroform, dichloromethane, acetone or their deuterated analogues were examined as substitutes for Freon‐11 in the electrophilic synthesis of 6‐[¹⁸F]fluoro‐L ‐DOPA ([¹⁸F]FDOPA). CDCl₃, CD₂Cl₂ and C₃D₆O were found to be suitable solvents in this reaction, with the deuterated solvents providing significantly higher yields than Freon‐11. There were no differences among the solvents in the specific radioactivity, the radiochemical purity, the chemical purity or the microbiological quality of the final product. However, the radiochemical yield of [¹⁸F]FDOPA was increased when acetic acid was added to the precursor solution prior to the fluorination reaction. Copyright © 2009 John Wiley & Sons, Ltd.     

Radiosynthesis of 4‐[18F]fluoromethyl‐L‐phenylalanine and [18F]FET via a same strategy and automated synthesis module

Currently there is still a need for more potent amino acid analogues as tumour imaging agents for peripheral tumour imaging with PET as it was recently reported that the success of O‐(2′‐[¹⁸F]fluoroethyl)‐L ‐tyrosine ([¹⁸F]FET) is limited to brain, head and neck tumours. As the earlier described 2‐Amino‐3‐(2‐[¹⁸F]fluoromethyl‐phenyl)‐propionic acid (2‐[¹⁸F]FMP) suffered from intramolecular‐catalysed defluorination, we synthesized 2‐Amino‐3‐(4‐[¹⁸F]fluoromethyl‐phenyl)‐propionic acid (4‐[¹⁸F]FMP) as an alternative for tumour imaging with PET. Radiosynthesis of 4‐[¹⁸F]FMP, based on Br for [¹⁸F] aliphatic nucleophilic exchange, was performed with a customized modular Scintomics automatic synthesis hotbox^three system in a high overall yield of 30% and with a radiochemical purity of \gt 99%. 4‐[¹⁸F]FMP was found to be stable in its radiopharmaceutical formulation, even at high radioactivity concentrations. Additionally, for a comparative study, [¹⁸F]FET was synthesized using the same setup in 40% overall yield, with a radiochemical purity \gt 99%. The described automated radiosynthesis allows the production of two different amino acid analogues with minor alternations to the parameter settings of the automated system, rendering this unit versatile for both research and clinical practice. Copyright © 2009 John Wiley & Sons, Ltd.     

How to increase the reactivity of [18F]fluoroethyl bromide: [18F]fluoroethylation of amine,phenol and amide functional groups with [18F]FEtBr, [18F]FEtBr/NaI and [18F]FEtOTf

[¹⁸F]Fluoroethyl bromide ([¹⁸F]FEtBr) is a useful synthetic precursor to synthesize ¹⁸F‐labeled compounds. However, the lower reactivity of [¹⁸F]FEtBr with amine, phenol and amide functional groups than that of [¹¹C]CH₃I partly limits its wide application in the synthesis of [¹⁸F]fluoroethylated compounds. The aim of this study was to increase the reactivity of [¹⁸F]FEtBr with various nucleophilic substrates for PET tracers containing amine, phenol and amide moieties. The present strategies included (1) adding NaI into the reaction mixture of [¹⁸F]FEtBr and substrate, where [¹⁸F]FEtI is reversibly formed and becomes more reactive; (2) converting [¹⁸F]FEtBr into much more reactive [¹⁸F]FEtOTf, similar to conversion of [¹¹C]CH₃I into [¹¹C]CH₃OTf. By these efforts, the [¹⁸F]fluoroethylation efficiency of various substrates containing amine, phenol and amide groups with [¹⁸F]FEtBr/NaI and [¹⁸F]FEtOTf was significantly improved, compared with the corresponding reaction efficiency with [¹⁸F]FEtBr. Copyright © 2003 John Wiley & Sons, Ltd.     

自动化合成N-琥珀酰亚胺-4-[18F]氟苯甲酸酯

目的 合成18F同位素标记蛋白质、配体、多肽类的中间体N-琥珀酰亚胺-4-[18F]氟苯甲酸酯(18F-FB).方法 以乙基-4-三甲胺苯甲酸酯-三氟磺酸盐为反应前体,利用正电子发射断层成像(PET)显像药物2-氟-18-氟-2-脱氧-D-葡萄糖(18F-FDG)合成专用模块TRACERlab FX-FDG和多用合成模块TRACERlab FX-FN及其固相萃取系统,基于控制软件的改造,通过亲核取代、氢氧化钠水解、酯化反应"三步法"合成.结果 合成18F-FB的总放射性合成时间小于80 min,校正后放射化学产率(38±3)%(n=10),放射化学纯度＞99%,与标准品19F-FB行HPLC比对分析,在柱平均保留时间Tr=8.515 min,两者保留时间基本吻合.结论 此法可以成功合成18F-FB,合成工艺成熟稳定,完全实现了自动化合成,为成功实现18F同位素标记蛋白、多肽类大分子物质进而实现PET成像提供了良好条件.     

Synthesis of 2‐[18F]fluoroadenosine (2‐[18F]FAD) as potential radiotracer for studying malignancies by PET

2‐[¹⁸F]fluoroadenosine (2‐[¹⁸F]FAD), a potential radioligand for assessment of adenylate metabolism, was synthesized by carrier‐added and no‐carrier‐added procedures via nucleophilic radiofluorination of 2‐fluoroadenosine and 2‐iodoadenosine. The radiochemical yield, specific radioactivity and radiochemical purity of carrier‐added and no‐carrier‐added 2‐[¹⁸F]FAD were 5%, 22–30 mCi/µmol and 99%, and 0.5%, 1200–1700 mCi/µmol and 99%, respectively. Copyright © 2006 John Wiley & Sons, Ltd.     

Simplified synthesis of N‐(3‐[18F]fluoropropyl)‐2β‐carbomethoxy‐3β‐(4‐fluorophenyl)nortropane ([18F]β‐CFT‐FP) using [18F]fluoropropyl tosylate as the labelling reagent

A synthesis method has been developed for the labelling of N‐(3‐[¹⁸F]fluoropropyl)‐2β‐carbomethoxy‐3β‐(4‐fluorophenyl)nortropane ([¹⁸F]β‐CFT‐FP), a potential radioligand for visualization of the dopamine transporters by positron emission tomography. The two‐step synthesis includes preparation of [¹⁸F]fluoropropyl tosylate and its use without purification in the fluoroalkylation of 2β‐carbomethoxy‐3β‐(4‐fluorophenyl)nortropane (nor‐β‐CFT). The final product is purified by HPLC. Optimization of the two synthesis steps resulted in a greater than 30% radiochemical yield of [¹⁸F]β‐CFT‐FP (decay corrected to end of bombardment). The synthesis time including HPLC‐purification was approximately 90 min. The radiochemical purity of the final product was higher than 99% and the specific radioactivity at the end of synthesis was typically 20 GBq/µmol. In comparison to alkylation by [¹⁸F]fluoropropyl bromide, the procedure described here results in an improved overall radiochemical yield of [¹⁸F]β‐CFT‐FP in a shorter time. Copyright © 2005 John Wiley & Sons, Ltd.     

Application of n.c.a. 4‐[18F]fluorophenol in diaryl ether syntheses of 2‐(4‐[18F]fluorophenoxy)‐benzylamines

The availability of no‐carrier‐added (n.c.a.) 4‐[¹⁸F]fluorophenol offers the possibility of introducing the 4‐[¹⁸F]fluorophenoxy moiety into potential radiopharmaceuticals. Besides alkyl–aryl ether synthesis using n.c.a. 4‐[¹⁸F]fluorophenol the diaryl ether coupling is an attractive synthetic method to enlarge the spectrum of interesting labelling procedures. As examples the syntheses of n.c.a. 2‐(4‐[¹⁸F]fluorophenoxy)‐N,N‐dimethylbenzylamine and n.c.a. 2‐(4‐[¹⁸F]fluorophenoxy)‐N‐methylbenzylamine were realized by an Ullmann ether synthesis of corresponding 2‐bromobenzoic acid amides using tetrakis(acetonitrile)copper(I) hexafluorophosphate as catalyst and a subsequent reduction of the amides formed. The radiochemical yield of the coupling varied between 5 and 65% based on labelled 4‐[¹⁸F]fluorophenol. Both compounds are structural analogues of recently published radiotracers for imaging the serotonin reuptake transporter sites (SERT). However, in vitro binding assays of both molecules showed only a low affinity towards monoamine transporters. Copyright © 2004 John Wiley & Sons, Ltd.     

Hydroacylation of 4‐[18F]fluorobenzaldehyde: a novel method for the preparation of 4′‐[18F]phenylketones

To assess the potential of intermolecular hydroacylation reactions as a new fluorine‐18 labeling method, model reactions of [¹⁸F]fluorobenzaldehyde with three different olefins (1‐hexene ( 2a ), allylbenzene ( 2b ), and 3‐phenoxypropene ( 2c )) in the presence of Wilkinson's catalyst were performed. The procedure gave high radiochemical yields (38–62%) of [¹⁸F]fluorophenylketones with short reaction times (15 min). The intermolecular hydroacylation reaction provides a new method for the preparation of fluorine‐18 labeled compounds. Copyright © 2002 John Wiley & Sons, Ltd.     

A fully automated synthesis of [18F]‐FEAU and [18F]‐FMAU using a novel dual reactor radiosynthesis module

2′‐Deoxy‐2′‐[¹⁸F]fluoro‐5‐substituted‐1‐β‐D ‐arabinofuranosyluracils, including 2′‐deoxy‐2′‐[¹⁸F]fluoro‐5‐methyl‐1‐β‐D ‐arabinofuranosyluracil [¹⁸F]FMAU and [¹⁸F]FEAU are established radiolabeled probes to monitor cellular proliferation and herpes simplex virus type 1 thymidine kinase (HSV1‐tk) reporter gene expression with positron emission tomography. For clinical applications, a fully automated CGMP‐compliant radiosynthesis is necessary for production of these probes. However, due to multiple steps in the synthesis, no such automated synthetic protocols have been developed. We report here a fully automated synthesis of [¹⁸F]‐FEAU and [¹⁸F]‐FMAU on a prototype dual reactor module TRACERlab FX FN. The synthesis was performed by using a computer‐programmed standard operating procedure, and the product was purified on a semipreparative high‐performance liquid chromatography (HPLC) integrated with the synthesis module using 12% EtOH in 50 mM Na₂HPO₄. Finally, the percentage of alcohol was adjusted to 7% by adding Na₂HPO₄ and filtered through a Millipore filter to make dose for human. The radiochemical yield on the fluorination was 40±10% (n=10), and the overall yields were 4±1% (d. c.), from the end of the bombardment; [¹⁸F]FEAU (n=7) and [¹⁸F]FMAU (n=3). The radiochemical purity was >99%, specific activity was 1200–1300 mCi/µmol. The synthesis time was 2.5 h. This automated synthesis should be suitable for production of [¹⁸F]FIAU, [¹⁸F]FFAU, [¹⁸F]FCAU, [¹⁸F]FBAU and other 5‐substitued thymidine analogues. Copyright © 2009 John Wiley & Sons, Ltd.     

Automated radiosynthesis of N‐(4‐[18F]fluorobenzyl)‐2‐bromoacetamide: an F‐18‐labeled reagent for the prosthetic radiolabeling of oligonucleotides

The potential for radiolabeled antisense oligonucleotides to image gene expression combined with the enhanced resolution of positron‐emission tomography justifies the continued interest in the development of oligonucleotides tagged with positron‐emitting radionuclides. The radiolabeling of oligonucleotides is a multi‐step process and may require handling large amounts of radioactivity initially. A previously reported method for radiolabeling oligonucleotides with N‐(4‐[¹⁸F]fluorobenzyl)‐2‐bromoacetamide was adapted for use in a commercially available automated synthesis unit by linking two reaction trains. The yield of N‐(4‐[¹⁸F]fluorobenzyl)‐2‐bromoacetamide ranged from 3 to 18% and the synthesis was completed within 1 h. Challenges in using this unit included the maintenance of anhydrous conditions for the effective reduction of 4‐[¹⁸F]fluorobenzonitrile. Preliminary results indicated that a mean yield of 36% could be obtained upon incubation of an oligonucleotide with N–(4‐[¹⁸F]fluorobenzyl)‐2‐bromoacetamide. The entire synthesis could be performed within 3 h. Copyright © 2008 John Wiley & Sons, Ltd.     

Radiosynthesis and ‘click’ conjugation of ethynyl‐4‐[18F]fluorobenzene — an improved [18F]synthon for indirect radiolabeling

Reproducible methods for [¹⁸F]radiolabeling of biological vectors are essential for the development of new [¹⁸F]radiopharmaceuticals. Molecules such as carbohydrates, peptides and proteins are challenging substrates that often require multi‐step indirect radiolabeling methods. With the goal of developing more robust, time saving, and less expensive procedures for indirect [¹⁸F]radiolabeling of such molecules, our group has synthesized ethynyl‐4‐[¹⁸F]fluorobenzene ([¹⁸F]2, [¹⁸F]EYFB) in a single step (14 ± 2% non‐decay corrected radiochemical yield (ndc RCY)) from a readily synthesized, shelf stable, inexpensive precursor. The alkyne‐functionalized synthon [¹⁸F]2 was then conjugated to two azido‐functionalized vector molecules via CuAAC reactions. The first ‘proof of principle’ conjugation of [¹⁸F]2 to 1‐azido‐1‐deoxy‐β‐d ‐glucopyranoside (3) gave the desired radiolabeled product [¹⁸F]4 in excellent radiochemical yield (76 ± 4% ndc RCY (11% overall)). As a second example, the conjugation of [¹⁸F]2 to matrix‐metalloproteinase inhibitor (5), which has potential in tumor imaging, gave the radiolabeled product [¹⁸F]6 in very good radiochemical yield (56 ± 12% ndc RCY (8% overall)). Total preparation time for [¹⁸F]4 and [¹⁸F]6 including [¹⁸F]F^? drying, two‐step reaction (nucleophilic substitution and CuAAC conjugation), two HPLC purifications, and two solid phase extractions did not exceed 70 min. The radiochemical purity of synthon [¹⁸F]2 and the conjugated products, [¹⁸F]4 and [¹⁸F]6, were all greater than 98%. The specific activities of [¹⁸F]2 and [¹⁸F]6 were low, 5.97 and 0.17 MBq nmol^?1, respectively.     

Microfluidic radiosynthesis and biodistribution of [18F] 2‐(5‐fluoro‐pentyl)‐2‐methyl malonic acid

Microfluidics technology has emerged as a powerful tool for the radiosynthesis of positron emission tomography (PET) and single‐photon emission computed tomography radiolabeled compounds. In this work, we have exploited a continuous flow microfluidic system (Advion, Inc., USA) for the [¹⁸F]‐fluorine radiolabeling of the malonic acid derivative, [¹⁸F] 2‐(5‐fluoro‐pentyl)‐2‐methyl malonic acid ([¹⁸F]‐FPMA), also known as [¹⁸F]‐ML‐10, a radiotracer proposed as a potential apoptosis PET imaging agent. The radiosynthesis was developed using a new tosylated precursor. Radiofluorination was initially optimized by manual synthesis and served as a basis to optimize reaction parameters for the microfluidic radiosynthesis. Under optimized conditions, radio‐thin‐layer chromatography analysis showed 79% [¹⁸F]‐fluorine incorporation prior to hydrolysis and purification. Following hydrolysis, the [¹⁸F]‐FPMA was purified by C18 Sep‐Pak, and the final product was analyzed by radio‐HPLC (high‐performance liquid chromatography). This resulted in a decay‐corrected 60% radiochemical yield and ≥98% radiochemical purity. Biodistribution data demonstrated rapid blood clearance with less than 2% of intact [¹⁸F]‐FPMA radioactivity remaining in the circulation 60 min post‐injection. Most organs showed low accumulation of the radiotracer, and radioactivity was predominately cleared through kidneys (95% in 1 h). Radio‐HPLC analysis of plasma and urine samples showed a stable radiotracer at least up to 60 min post‐injection.