“In‐loop” 18F‐fluorination: A proof‐of‐concept study

There is a great demand to develop more cost‐efficient and robust manufacturing processes for fluorine‐18 (¹⁸F) labelled compounds and radiopharmaceuticals. Herein, we present to our knowledge the first radiofluorination “in‐loop,” where [¹⁸F]triflyl fluoride was used as the labelling agent. Initial development of the “in‐loop” [¹⁸F]fluorination method was optimized by reacting [¹⁸F]triflyl fluoride with 1,4‐dinitrobenzene to form [¹⁸F]1‐fluoro‐4‐nitrobenzene. This methodology was then applied for the syntheses of two well‐known radiopharmaceuticals, namely, [¹⁸F]T807 for imaging of tau protein and [¹⁸F]FEPPA for imaging the translocator protein 18 KDa. Both radiotracers were synthesized and formulated using an automated radiosynthesis module with nondecay corrected radiochemical yields of 27% and 29% (relative [¹⁸F]F^?), respectively. The overall syntheses times for [¹⁸F]T807 and [¹⁸F]FEPPA were 65 and 55 minutes, respectively. In these cases, our “in‐loop” radiofluorination methodology enabled us to obtain equal or superior yields compared with conventional reactions in a vial. The radiochemical purities were more than 99%, and the molar activities were more than 350 GBq/μmol at the end‐of‐synthesis for both radiotracers. This novel method is simple, efficient, and allows for a reliable production of radiofluorinated compounds and radiopharmaceuticals.     

Preparation of fluorine‐18‐labelled fluoromisonidazole using two different synthesis methods

¹⁸F‐labelled fluoromisonidazole [1H‐1‐(3‐[¹⁸F]fluoro‐2‐hydroxypropyl)‐2‐nitroimida‐zole; ([¹⁸F]FMISO)] is used as an in vivo marker of hypoxic cells in tumours and ischaemic areas of the heart and the brain. The compound plays an important role in evaluating the oxygenation status in tumours during radiotherapy. In this paper, we report experiments carried out in our laboratory in synthesizing [¹⁸F]FMISO using two different methods. The first method (I) for the [¹⁸F]FMISO synthesis was the fluorination of (2R)‐(?)‐glycidyl tosylate to [¹⁸F]epifluorohydrin. The subsequent nucleophilic ring opening, achieved with 2‐nitroimidazole, leads to labelled FMISO. The second method (II) was the fluorination of the protected precursor 1‐(2′‐nitro‐1′‐imidazolyl)‐2‐O‐tetrahydropyranyl‐3‐O‐toluenesulphonyl‐propanediol, followed by a rapid removal of the protecting group. With the first method, the radiochemical yield was about 10% at the end of the synthesis (EOS), and the radiochemical purity was over 99%. The radiochemical yield in the second method was 21% (EOS) on an average, and the radiochemical purity was over 97%. When an automated commercial synthesis module was used with method II, slightly better and more reproducible yields were achieved. The improvement in the synthesis yield with the automated apparatus will be valuable when working with high activities, and therefore it is under further development. Copyright © 2003 John Wiley & Sons, Ltd.     

Fast indirect fluorine‐18 labeling of protein/peptide using the useful 6‐fluoronicotinic acid‐2,3,5,6‐tetrafluorophenyl prosthetic group: A method comparable to direct fluorination

Fluorine‐18 labeling of biomolecules is mostly performed by an indirect labeling method using a prosthetic group. Fluorine‐18 labeled 6‐fluoronicotinic acid‐2,3,5,6‐tetrafluorophenyl ester is a useful prosthetic group to radiolabel a protein. Recently, we reported an improved preparation of this prosthetic group. To test the conjugation efficiency of the labeled ester prepared by this method, we have performed conjugation reactions with a peptide, a protein, and a small molecule. Prostate‐specific membrane antigen targeting small molecule [¹⁸F]DCFPyL, αvβ3 integrin receptors targeting peptide [¹⁸F]c(RGDfK) and [¹⁸F]albumin were prepared in good radiochemical yields. The conjugation reactions were completed at 40°C to 50°C in 10 minutes. The overall radiochemical yield was 25% to 43% in 30 to 45 minutes.     

Design and synthesis of fluorine‐18 labeled matrix metalloproteinase inhibitors for cancer imaging

Matrix metalloproteinases (MMPs) are key enzymes involved in cancer invasion and metastasis. New ¹⁸F‐labeled MMP inhibitors ( 1a–c ) has been designed and synthesized for cancer imaging by positron emmision tomography. The precursors were synthesized in four steps starting from D ‐form of amino acids. Radiosynthesis of 1a–c were carried out by simple one‐pot synthesis. The resulting radiofluorinated MMP inhibitors were obtained in overall radiochemical yields of 13–43% (EOB, decay corrected) within 60–70 min (including final preparative HPLC separation). Copyright © 2002 John Wiley & Sons, Ltd.     

A general method for the fluorine‐18 labelling of fluoroquinolone antibiotics

Fluoroquinolones are an important class of antibiotic agents with a broad spectrum of antibacterial activity. Labelling of fluoroquinolones with fluorine‐18 is of interest for the performance of pharmacokinetic measurements and the visualization of bacterial infections in humans with positron emission tomography. A two‐step radiosynthetic pathway to prepare fluorine‐18‐labelled ciprofloxacin (1‐cyclopropyl‐6‐[¹⁸F]fluoro‐1,4‐dihydro‐4‐oxo‐7‐(1‐piperazinyl)‐quinoline‐3‐carboxylic acid) has previously been developed. In the present work this approach was applied to the preparation of the structurally related compounds [¹⁸F]norfloxacin (1‐ethyl‐6‐[¹⁸F]fluoro‐1,4‐dihydro‐4‐oxo‐7‐(1‐piperazinyl)‐quinoline‐3‐carboxylic acid) and [¹⁸F]pefloxacin (1‐ethyl‐6‐[¹⁸F]fluoro‐1,4‐dihydro‐7‐(4‐methyl‐1‐piperazinyl)‐4‐oxo‐quinoline‐3‐carboxylic acid). The first step of the radiosynthesis consisted of a ¹⁸F for ¹⁹F exchange reaction on a 7‐chloro‐substituted precursor molecule, followed by coupling reactions with the amines piperazine or 1‐methylpiperazine. Starting from 51–58 GBq of [¹⁸F]fluoride 1.9–2.0 GBq of [¹⁸F]norfloxacin or [¹⁸F]pefloxacin, ready for intravenous injection, could be obtained in a synthesis time of 130 min (3.5–3.8% overall radiochemical yield). Moreover, the preparation of [¹⁸F]levofloxacin ((‐)‐(S)‐9‐[¹⁸F]fluoro‐2,3‐dihydro‐3‐methyl‐10‐(4‐methyl‐1‐piperazinyl)‐7‐oxo‐7H‐pyrido[1,2,3‐de]‐1,4‐benzoxazine‐6‐carboxylicacid) was attempted but failed to afford the desired product in practical amounts. Copyright © 2003 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.     

Expedient synthesis of [18F]‐labeled α‐trifluoromethyl ketones

Several [¹⁸F]‐labeled α‐trifluoromethyl ketones have been synthesized. Reactions of 2,2‐difluoro‐1‐aryl‐1‐trimethylsiloxyethenes ( 1a–d ) with [¹⁸F]‐F₂ at low temperature produced [¹⁸F]‐labeled α‐trifluoromethyl ketones ( 2a–d ). Radio‐labeled products were isolated by purification with column chromatography in 22–28% yields, decay corrected (d.c.) in three runs per compound. Radiochemical purity was >99% with specific activities 15–20 GBq/mmol at the end of synthesis (EOS). The synthesis time was 35–40 min from the end of bombardment (EOB). This one‐step simple method is highly useful for the radiochemical synthesis of potential biologically active [¹⁸F]‐labeled α‐trifluoromethyl ketones for PET imaging. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of [18F]‐labeled 2′‐deoxy‐2′‐fluoro‐5‐methyl‐1‐β‐D‐arabinofuranosyluracil ([18F]‐FMAU)

Synthesis of 2′‐deoxy‐2′‐[¹⁸F]fluoro‐5‐methyl‐1‐β‐D‐arabinofuranosyluracil ([¹⁸F]‐FMAU) is reported. 2‐Deoxy‐2‐[¹⁸F]fluoro‐1,3,5‐tri‐O‐benzoyl‐α‐D‐arabinofuranose 2 was prepared by the reaction of the respective triflate 1 with tetrabutylammonium[¹⁸F]fluoride. The fluorosugar 2 was converted to its 1‐bromo‐derivative 3 and coupled with protected thymine 4 . The crude product mixture ( 5a and 5b ) was hydrolyzed in base and purified by HPLC to obtain the radiolabeled FMAU 6a . The radiochemical yield of 6a was 20–30% decay corrected (d.c.) in four steps with an average of 25% in four runs. Radiochemical purity was >99% and average specific activity was 2300 mCi/μmol at the end of synthesis (EOS). The synthesis time was 3.5–4.0 h from the end of bombardment (EOB). Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis of fluorine‐18‐labelled 5‐ and 6‐fluoro‐2‐pyridinamine

A one‐pot radiosynthesis method to prepare the new fluorine‐18‐labelled fluoropyridine derivatives 5‐[¹⁸F]fluoro‐2‐pyridinamine and 6‐[¹⁸F]fluoro‐2‐pyridinamine in two to three reaction steps was developed. The first step consisted of no‐carrier‐added nucleophilic aromatic substitution of commercially available halogen‐substituted 2‐pyridinecarboxamide or 2‐pyridinecarbonitrile derivatives with K[¹⁸F]F‐K₂₂₂ in DMSO at 150–180°C. The [¹⁸F]fluoride incorporation yields ranged from 67 to 98% for all studied precursor molecules. It is remarkable that 5‐bromo‐2‐pyridinecarbonitrile gave almost quantitative [¹⁸F]fluoride incorporation at the meta‐position (5‐position) of the pyridine ring after only 5 min of heating at 150°C. After base‐catalysed hydrolysis of the [¹⁸F]fluorinated pyridinecarbonitriles into their corresponding carboxamides, the latter were transformed in a Hofmann‐type rearrangement reaction into the respective amines by treatment of crude reaction mixtures with bromine and aqueous base (20–30% conversion yield). Reaction mixtures were purified by reversed‐phase semipreparative HPLC followed by strong cation exchange solid‐phase extraction to afford 5‐[¹⁸F]fluoro‐2‐pyridinamine and 6‐[¹⁸F]fluoro‐2‐pyridinamine in non‐decay‐corrected radiochemical yields of 6–10% in a total synthesis time of 83–112 min. The preparation of 5‐[¹⁸F]fluoro‐2‐pyridinamine is one of very few examples demonstrating the feasibility of nucleophilic meta‐[¹⁸F]fluorination of a pyridine derivative. Both 5‐[¹⁸F]fluoro‐2‐pyridinamine and 6‐[¹⁸F]fluoro‐2‐pyridinamine are new potentially useful radiolabelled synthons for radiopharmaceutical chemistry. Copyright © 2006 John Wiley & Sons, Ltd.     

A general synthesis of 2′‐deoxy‐2′‐[18F]fluoro‐1‐β‐D‐arabinofuranosyluracil and its 5‐substituted nucleosides

Several 2′‐deoxy‐2′‐[¹⁸F]fluoro‐1‐β‐D‐arabinofuranosyluracil derivatives have been synthesized. Coupling of 1‐bromo‐2‐deoxy‐2‐[¹⁸F]fluoro‐3,5‐di‐O‐benzoyl‐α‐D‐arabinofuranose 2 with protected uracil derivatives 3a–e followed by hydrolysis and high‐performance liquid chromatography purification produced the radiolabeled nucleosides 4a–e in 15–30% yield (d. c.), >99% radiochemical purity and 55.5–103.6 GBq/µmol specific activities. Copyright © 2003 John Wiley & Sons, Ltd.     

[18F]FPyKYNE,a fluoropyridine‐based alkyne reagent designed for the fluorine‐18 labelling of macromolecules using click chemistry

FPyKYNE (2‐fluoro‐3‐pent‐4‐yn‐1‐yloxypyridine) is a novel fluoropyridine‐based structure, designed for the fluorine‐18 labelling of macromolecules using copper‐catalysed Huisgen 1,3‐dipolar cycloaddition (click chemistry). FPyKYNE (non‐labelled as reference), as well as the 2‐bromo, 2‐nitro and 2‐trimethylammonium analogues (as precursors for labelling with fluorine‐18), was synthesized in 44, 95, 60 and 41%, respectively, from commercially available 5‐chloropent‐1‐yne and the appropriate 2‐substituted‐3‐hydroxypyridines. [¹⁸F]FPyKYNE was synthesized in one single radiochemical step by reaction of no‐carrier‐added K[¹⁸F]F‐Kryptofix^®222 (DMSO, 165°C, 3–5 min) followed by C‐18 SepPak cartridge pre‐purification and finally semi‐preparative HPLC purification on a Hewlett Packard SiO₂ Zorbax^® Rx‐SIL. Using the 2‐nitropyridine or the pyridin‐2‐yltrimethylammonium trifluoromethanesulphonate precursor for labelling (30 and 10 µmol, respectively), incorporation yields up to 90% were observed and 7.0–8.9 GBq (190–240 mCi) of [¹⁸F]FPyKYNE ([¹⁸F]‐1) could be isolated within 60–70 min (HPLC purification included), starting from a 37.0 GBq (1.0 Ci) [¹⁸F]fluoride batch (overall decay‐corrected and isolated yields: 30–35%). Copyright © 2008 John Wiley & Sons, Ltd.     

Teflon radiolysis as the major source of carrier in fluorine‐18

The practical upper limit of fluorine‐18 specific activity has remained constant for many years among cyclotron facilities internationally. Although there have been isolated reports of very high specific activity and hints concerning the sources of carrier, experiments designed to identify carrier sources have been inconclusive and largely ineffective. This report describes experiments to test the hypothesis that radiolysis of fluorinated components is a source of carrier fluoride. Controlled experiments were performed in which contributions of irradiated fluorinated components to the mass of synthesized [¹⁸F]fluorobenzaldehyde (FBA) were measured. There was clear correlation between irradiation of Teflon and carrier mass. There was an additive effect of carrier due to different fluoropolymer components. It was concluded that in typical target and radiosynthesis systems it is radiolysis of fluorinated material and not the material itself that generates a large majority of the carrier typically reported. All Teflon and other fluorinated materials in contact with the [¹⁸F]fluoride solution were removed. With no further efforts to reduce carrier fluoride, FBA produced from a modest irradiation attained a reduction in mass from over 500 nmol to 30 nmol, and an increase in specific activity from 0.1 TBq (3 Ci) to 1.9 TBq (51 Ci) per micromole. Copyright © 2009 John Wiley & Sons, Ltd.     

Temperature effects on the stereospecificity of nucleophilic fluorination: formation of trans‐[18F]4‐fluoro‐l‐proline during the synthesis of cis‐[18F]4‐fluoro‐l‐proline

Fluorine‐18 labeled (2S,4S)‐4‐fluoro‐l ‐proline (cis‐[¹⁸F]4‐FPro) has been reported to be a potential positron emission tomography tracer to study abnormal collagen synthesis occurring in pulmonary fibrosis, osteosarcomas, mammary and colon carcinomas. In this paper, we report the stereospecific radiofluorination of (2S,4R)‐N‐tert‐butoxycarbonyl‐4‐(p‐toluenesulfonyloxy) proline methyl ester (at 110°C) to produce diastereomerically pure cis‐[¹⁸F]4‐FPro in 38% radiochemical yield at the end of a 90‐min synthesis. Investigation of the effect of temperature on the stereospecificity of nucleophilic fluorination showed that diasteriomerically pure cis‐[¹⁸F]4‐FPro or trans‐[¹⁸F]4‐FPro was produced at lower temperatures (85°C–110°C) during the fluorination of (2S,4R) or (2S,4S) precursors, respectively. However, at higher temperatures (130°C–145°C), fluorination of (2S,4R) precursor produced a mixture of cis‐[¹⁸F]4‐FPro and trans‐[¹⁸F]4‐FPro diastereomers with cis‐[¹⁸F]4‐FPro as the predominant isomer. Hydrolysis of the purified fluorinated intermediate was carried out either in one step, using 2 m triflic acid at 145°C for 10 min, or in two steps where the intermediate was heated in 1 m HCl at 110°C for 10 min followed by stirring at room temperature in 1 N NaOH for 5 min. The aqueous hydrolysis mixture was loaded onto an anion exchange column (acetate form for one‐step hydrolysis) or an ion retardation column (two‐step hydrolysis) followed by a C₁₈ Sep‐Pak® (Waters Corporation, Milford, MA, USA). Pure cis‐[¹⁸F]4‐FPro was then eluted with sterile water. We also report that epimerization of cis‐[¹⁸F]4‐FPro occurs during the two‐step hydrolysis (H⁺ followed by OH^?) of the intermediate, resulting in 5 ± 3% trans‐[¹⁸F]4‐FPro, whereas the one‐step acid hydrolysis yielded pure cis‐[¹⁸F]4‐FPro in the final product. Copyright © 2011 John Wiley & Sons, Ltd.     

Fluorine‐18 labelling of oligonucleotides: Prosthetic labelling at the 5′‐end using the N‐(4‐[18F]fluorobenzyl)‐2‐bromoacetamide reagent

Labelled oligonucleotides are new imaging tools to study gene expression at the nucleic acid and protein levels. We have previously developed a universal method to label oligonucleotides at their 3′‐end with radiohalogens and particularly with fluorine‐18, the most widely used positron‐emitter, t_1/2: 109.8 min. Using the same strategy, we herein report the fluorine‐18 labelling of oligonucleotides at their 5′‐end. A 18‐mer 2′O‐methyl modified oligoribonucleotide, bearing a phosphorothioate group at its 5′‐end, was conjugated to our fluorine‐18‐labelled reagent N‐(4‐[¹⁸F]fluorobenzyl)‐2‐bromoacetamide. The whole synthetic procedure yielded up to 1 GBq of fluorine‐18‐labelled oligonucleotide with a specific radioactivity of 37–74 GBq/μmol in 160 min. Copyright © 2003 John Wiley & Sons, Ltd.     

Reaction of [18F]4‐fluorobenzenediazonium cations with cysteine or the cysteinyl group: preparation of 18F‐labeled S‐aryl‐cysteine and a radiolabeled peptide

A reaction route for the preparation of no‐carrier‐added (n.c.a.) [¹⁸F]S‐4‐fluorophenylcysteine 7 via the [¹⁸F]‐4‐fluorobenzenediazonium ion 4 is described. The key step in this radiosynthesis is the reaction of 4 with cysteine forming [¹⁸F]4‐fluorophenyldiazocysteine 6 , which is subsequently converted into 7 by irradiation with 366 nm light. 4 was synthesized by reacting 1,4‐dinitrobenzene 1 with [¹⁸F]‐fluoride in acetonitrile in a PEEK‐capillary in a microwave oven. After dilution of the reaction mixture with methanol, the resulting [¹⁸F]4‐fluoro‐1‐nitrobenzene 2 was submitted to reduction by means of H₂ with Pd on C catalyst. The resulting [¹⁸F]4‐fluoroaniline 3 was purified by HPLC and diazotized to 4 . The preparation of 4 was optimized with regard to yield and purity. The radiochemical yield of 6 was >90% (based on 3 ) while after UV irradiation and HPLC purification 45% of 7 (based on 3 ) was obtained (yields corrected for decay). The suitability of this method for labeling peptides with fluorine‐18 was demonstrated by application to the tripeptide, glutathione (GSH; γ‐L‐glutamyl‐L‐cysteinyglycine) 8 . Copyright © 2002 John Wiley & Sons, Ltd.     

The first enzymatic method for C–18F bond formation: the synthesis of 5′‐[18F]‐fluoro‐5′‐deoxyadenosine for imaging with PET

The use of the key enzyme involved in carbon–fluorine bond formation in Streptomyces cattleya catalysing the formation of 5′‐fluoro‐5′‐deoxyadenosine (5′‐FDA) from fluoride ion and S‐adenosyl‐l‐methionine (SAM) was explored for its potential application in fluorine‐18 labelling of the adenosine derivative. Enzymatic radiolabelling of [¹⁸F]‐5′‐FDA was successfully carried out starting from SAM and [¹⁸F]HF when the concentration of the enzyme preparation was increased from sub‐mg/ml values to mg/ml values. The purity of the enzyme had no measurable effect on the radiochemical yield of the reaction and the radiochemical purity of [¹⁸F]‐5′‐FDA. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of 3′‐deoxy‐3′‐[18F]fluoro‐1‐β‐D‐xylofuranosyluracil ([18F]‐FMXU) for PET

The synthesis of a pyrimidine analog, 3′‐deoxy‐3′‐[¹⁸F]‐fluoro‐1‐β‐D ‐xylofuranosyluracil ([¹⁸F]‐FMXU) is reported. 5‐Methyluridine 1 was converted to its di‐methoxytrityl derivatives 2 and 3 as a mixture. After separation the 2′,5′‐di‐methoxytrityluridine 2 was converted to its 3′‐triflate 4 followed by derivatization to the respective N³‐t‐Boc product 5 . The triflate 5 was reacted with tetrabutylammonium[¹⁸F]fluoride to produce 6 , which by acid hydrolysis yielded compound 7 . The crude preparation was purified by HPLC to obtain the desired product [¹⁸F]‐FMXU. The radiochemical yields were 25–40% decay corrected (d. c.) with an average of 33% in four runs. Radiochemical purity was >99% and specific activity was >74 GBq/µmol at the end of synthesis (EOS). The synthesis time was 67–75 min from the end of bombardment (EOB). Copyright © 2005 John Wiley & Sons, Ltd.     

The synthesis of a benzamidine‐containing NR2B‐selective NMDA receptor ligand labelled with tritium or fluorine‐18

A novel tritium or flourine‐18‐labelled benzamidine‐containing NR2B‐selective NMDA receptor ligand has been synthesized. This compound was designed to contain the fluoromethoxy group to allow for the synthesis of a high specific activity, fluorine‐18‐labelled PET tracer for imaging studies of the NR2B receptor. In addition to the fluorine‐18‐labelled compound, this compound was also tritium labelled. The tritiated ligand (11 Ci/mmol) was synthesized by a gas tritiation reaction of an aryl bromide precursor. The fluorine‐18 ligand (2916 Ci/mmol), which was deuterated in the fluoromethoxy group to aid in metabolic stability, was synthesized by alkylating a phenolic precursor with [¹⁸F]fluoromethylbromide‐d₂. Copyright © 2004 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.     

Synthesis and structural identification of fluorine‐18 labeled parathyroid hormone

Parathyroid hormone (PTH) is an 84 amino acid peptide hormone that plays a key role in bone and mineral metabolism. The biological actions of PTH are mediated via the N‐terminal PTH(1–34) fragment, serving as the PTH receptor‐binding sequence, and which is therefore used clinically to treat conditions of low bone mass such as osteoporosis. In this study, PTH(1–34) was conjugated with non‐radioactive (stable F isotope) N‐succinimidyl 4‐fluorobenzoate (SFB) leading to three isomeric mono‐fluorobenzoated (FBz) PTH followed by Liquid chromatography‐Tandem mass spectrometry (LC‐MS/MS) assisted structural identification. Corresponding [¹⁸F]SFB‐labeled PTH derivatives were prepared respectively and the Lys¹³ site‐specific labeled [¹⁸F]FBz PTH was isolated by HPLC with radiochemical purity >99% and specific activity of 2.78 GBq/µmol, suitable for future application with in vivo pharmacokinetic/pharmacodynamic studies of PTH, using preclinical Positron Emission Tomography Computed Tomography (PET/CT) imaging.