Efficient Radiosynthesis of 2-[18F]Fluoroadenosine: A New Route to 2-[18F]Fluoropurine Nucleosides

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Rapid and efficient synthesis of [18F]fluoronicotinamides, [18F]fluoroisonicotinamides and [18F]fluorobenzamides as potential pet radiopharmaceuticals for melanoma imaging

In an attempt to simplify nucleophilic radiofluorination reactions to be amenable for automation, a series of [¹⁸F]fluoronicotinamides, [¹⁸F]fluoroisonicotinamides and [¹⁸F]fluorobenzamides were synthesized using one‐step synthetic approach involving displacement reactions on trimethylammonium‐nicotinamide, trimethylammonium‐isonicotinamide and trimethylammonium‐benzamide precursors. Based on starting [¹⁸F]‐fluoride, radiochemical yields and purities were found to be greater than 90 and 97%, respectively, within 20 min synthesis time and, without high‐performance liquid chromatography purification. This synthetic approach holds great promise as a rapid and simple method for the automated radiofluorination of [¹⁸F]fluoronicotinamides, [¹⁸F]fluoroisonicotinamides and [¹⁸F]fluorobenzamides with high radiochemical yield and very short preparation time. Copyright © 2011 John Wiley & Sons, Ltd.     

Radiosyntheses and reactivities of novel [18F]2‐fluoroethyl arylsulfonates

[¹⁸F]2‐Fluoroethyl tosylate ([¹⁸F]FEOX, X=Ts) is widely used for labeling radiotracers for positron emission tomography (PET). Little work has been reported on syntheses of other [¹⁸F]2‐fluoroethyl arylsulfonates ([¹⁸F]FEOX) that bear a less electron‐rich aryl group, even though these might offer enhanced reactivities. Thus, a series of novel [¹⁸F]FEOX (X=benzenesulfonyl, brosyl, nosyl, 3,4‐dibromobenzenesulfonyl) were synthesized and reactivities compared to [¹⁸F]FEOTs. Precursors for radiolabeling (bis‐ethylene glycol arylsulfonates) and reference FEOX were synthesized (alcohol+arylsulfonyl chloride+KOSiMe₃ in THF). Regardless of substitution pattern, [¹⁸F]FEOX (110°C, 5 min, acetonitrile) were obtained in similar decay‐corrected isolated radiochemical yields (RCY; 47–53%). All [¹⁸F]FEOX gave excellent RCYs (64–87%) of the dopamine uptake radioligand, [¹⁸F]FECNT (130°C, 10 min, acetonitrile). The 3,4‐dibromobenzensulfonate gave the highest RCY of [¹⁸F]FECNT (87%) and this HPLC‐purified labeling agent was used directly for efficient [¹⁸F]FECNT production. When the secondary aniline of an amyloid probe (HM‐IMPY) or p‐nitrophenol was reacted with [¹⁸F]FEOX, RCYs were appreciably higher for brosylate and nosylate than for tosylate, while 3,4‐dibromobenzenesulfonate again gave the highest RCY. Owing to the high reactivity of the new [¹⁸F]FEOX and their ease of syntheses via stable precursors, such agents (particularly 3,4‐dibromobenzenesulfonate) should be considered as alternatives to [¹⁸F]FEOTs. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of an 18F‐labeled cyclin‐dependent kinase‐2 inhibitor

The radiosynthesis of N‐(5‐(((5‐(tert‐butyl)oxazol‐2‐yl)methyl)thio)thiazol‐2‐yl)‐4‐[¹⁸F]fluoro‐benzamide [¹⁸F]2 as a potential radiotracer for molecular imaging of cyclin‐dependent kinase‐2 (CDK‐2) expression in vivo by positron emission tomography is described. Two different synthesis routes were envisaged. The first approach followed direct radiofluorination of respective nitro‐ and trimethylammonium substituted benzamides as labeling precursors with no‐carrier‐added (n.c.a.) [¹⁸F]fluoride. A second synthesis route was based on the acylation reaction of 2‐aminothiazole derivative with labeling agent [¹⁸F]SFB. Direct radiofluorination afforded ¹⁸ F‐labeled CDK‐2 inhibitor in very low yields of 1%–3%, whereas acylation reaction with [¹⁸F]SFB gave ¹⁸ F‐labeled CDK‐2 inhibitor [¹⁸ F]2 in high yields of up to 85% based upon [¹⁸ F]SFB during the optimization experiments. Large scale preparation afforded radiotracer [¹⁸ F]2 in isolated radiochemical yields of 37%–44% (n = 3, decay‐corrected) after HPLC purification within 75 min based upon [¹⁸ F]SFB. This corresponds to a decay‐corrected radiochemical yield of 13%–16% based upon [¹⁸F]fluoride. The radiochemical purity exceeded 95% and the specific activity was determined to be 20 GBq/µmol. Copyright © 2011 John Wiley & Sons, Ltd.     

2-Amino-2′-[18F]fluorobenzhydrols,intermediates for the synthesis of [2′-18F]-1,4-benzodiazepine-2-ones

A method for synthesizing ¹⁸F-labelled 2-amino-2′-fluorobenzhydrols under nocarrier-added conditions for use as radiolabelled intermediates in the synthesis of[2′-¹⁸F]-1,4-benzodiazepine-2-ones is presented. Anilinodichloroborane reagents were formed by the reaction of boron trichloride with 4-chloro-N-methylaniline, 6a , 4-nitro-N-methylaniline, 6b , 4-nitro-N-ethylaniline, 6c , and 4-chloro-N-(2,2,2-trifluoroethyl)aniline, 6d . 2-[¹⁸F]Fluorobenzaldehyde, 5 , synthesized in 55–70% yields by the nucleophilic aromatic substitution of 2-nitrobenzaldehyde with the Kryptofix/K⁺ complex of [¹⁸F]F⁻, was subsequently reacted with the anilinodichloroborane coupling reagents with aromatic substitution occurring ortho to the amino group. The resulting 2-amino-2′-[¹⁸F]fluorobenzhydrols, 7a - 7d , were produced in conversions of 60–95% with reaction time ⩽ 10 min at room temperature or 60°C, depending on the aniline used. The total synthesis time, including evaporation of the target water, was 60–65 min. The total radiochemical conversions were of the order of 50–65% for 7a - 7c and 35–45% for 7d , decay-corrected and based on [¹⁸F]F⁻.     

Radiosynthesis of 3‐(3‐[18F]fluoropropoxy)‐4‐(benzyloxy)‐N‐[(1‐dimethylaminocyclopentyl)methyl]‐5‐methoxybenzamide,a potential PET radiotracer for the glycine transporter GlyT‐2

The recently described selective and potent GlyT2 antagonist, 4‐benzyloxy‐3,5‐dimethoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide (IC₅₀=16 nM) provided an important additional tool to further characterize GlyT2 pharmacology. In order to identify an effective PET radioligand for in vivo assessment of the GlyT‐2 transporter, 3‐(3‐[¹⁸F]fluoropropoxy)‐4‐(benzyloxy)‐N‐((1‐dimethylaminocyclopentyl) methyl)‐5‐methoxybenzamide ([¹⁸F] 3 ), a novel analog of 4‐benzyloxy‐3,5‐dimethoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide was synthesized using a one‐pot, two‐step method. The NCA radiofluorination of 1,3‐propanediol di‐p‐tosylate in the presence of K₂CO₃ and Kryptofix‐222 in acetonitrile gave 81% 3‐[¹⁸F]fluoropropyl tosylate, which was subsequently coupled with 4‐benzyloxy‐3‐hydroxy‐5‐methoxy‐N‐[(1‐dimethylaminocyclopentyl) methyl]benzamide in the same reaction vessel. Solvent extraction and HPLC (Eclipse XDB‐C8 column, 80/20/0.1 MeOH/H₂O/Et₃N, 3.0 ml/min) gave [¹⁸F] 3 in 98.5% radiochemical purity. The radiochemical yield was determined to be 14.0–16.2% at EOS, and the specific activity was 1462±342 GBq/µmol. The time of synthesis and purification was 128 min. The final product was prepared as a sterile saline solution suitable for in vivo use. Copyright © 2006 John Wiley & Sons, Ltd.     

Two‐step radiosynthesis of [18F]FE‐β‐CIT and [18F]PR04.MZ

The cocaine‐derived dopamine reuptake inhibitors FE‐β‐CIT (8‐(2‐fluoroethyl)‐3‐(4‐iodophenyl)‐8‐azabicyclo[3.2.1]octane‐2‐carboxylic acid methyl ester) (1) and PR04.MZ(8‐(4‐fluorobut‐2‐ynyl)‐3‐p‐tolyl‐8‐azabicyclo[3.2.1]octane‐2‐carboxylic acid methyl ester) (2) were labelled with ¹⁸F‐fluorine using a two‐step route. 2‐[¹⁸F]Fluoroethyltosylate and 4‐[¹⁸F]fluorobut‐2‐yne‐1‐yl tosylate were used as labelling reagents, respectively. Radiochemically pure (>98%) [¹⁸F]FE‐β‐CIT and [¹⁸F]PRD04.MZ (32–86 GBq/µmol) were obtained after a synthesis time of 100 min in about 25% non‐decay‐corrected overall yield.     

Selective synthesis of L-2-[18F]fluoro-alpha-methylphenylalanine via copper-mediated 18F-fluorination of (mesityl)(aryl)iodonium salt

L-2-[¹⁸F]fluoro-alpha-methylphenylalanine (2-[¹⁸F]FAMP) is a promising amino acid tracer for positron emission tomography (PET) imaging, yet the low production yield of direct electrophilic radiofluorination with [¹⁸F]F₂ necessitates further optimization of the radiolabeling process. This paper describes a two-step preparation method for L-2-[¹⁸F]fluoro-alpha-methylphenylalanine (2-[¹⁸F]FAMP) starting from [¹⁸F]fluoride. The (Mesityl)(L-alpha-methylphenylalanine)-2-iodonium tetrafluoroborate precursors with various protecting groups were prepared. The copper-mediated ¹⁸F-fluorination of the iodonium salt precursors successfully produced 2-[¹⁸F]FAMP. The highest radio chemical conversion of 57.6% was noted with N-Piv-protected (mesityl)(aryl)iodonium salt in the presence of 5 equivalent of Cu (OTf)₂. Subsequent deprotection with 57% hydrogen iodide produced 2-[¹⁸F]FAMP within 120 min in 21.4 ± 11.7% overall radiochemical yield with >95% radiochemical purity and an enantiomeric excess >99%. The obtained 2-[¹⁸F]FAMP showed comparable biodistribution profiles in normal mice with that of the carrier-added 2-[¹⁸F]FAMP. These results indicate that usefulness of copper mediated ¹⁸F-fluorination for the production of 2-[¹⁸F]FAMP, which would facilitate clinical translation of the promising tumor specific amino acid tracer. Individual facilities could adopt either production method based on radioactivity demand and equipment availability.     

Automated radiosynthesis of the adenosine A2A receptor-targeting radiotracer [18F]FLUDA

[¹⁸F] FLUDA is a selective radiotracer for in vivo imaging of the adenosine A_2A receptor (A_2AR) by positron emission tomography (PET). Promising preclinical results obtained by neuroimaging of mice and piglets suggest the translation of [¹⁸F] FLUDA to human PET studies. Thus, we report herein a remotely controlled automated radiosynthesis of [¹⁸F] FLUDA using a GE TRACERlab FX2 N radiosynthesizer. The radiotracer was obtained by a one-pot two-step radiofluorination procedure with a radiochemical yield of 9±1%, a radiochemical purity of ≥99%, and molar activities in the range of 69–333 GBq/μmol at the end of synthesis within a total synthesis time of approx. 95 min (n = 16). Altogether, we successfully established a reliable and reproducible procedure for the automated production of [¹⁸F] FLUDA.     

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.     

Direct radiofluorination of [18F]MH.MZ for 5‐HT2A receptor molecular imaging with PET

Imaging the serotonin 2A neuroreceptor with positron emission tomography has been carried out with [¹¹C]MDL 100907 and [¹⁸F]altanserin for years. Recently, the MDL 100907 analogue [¹⁸F]MH.MZ was developed by combining the increased selectivity profile of MDL 100907 and the favourable radiophysical properties of fluorine‐18. Here, we want to report the synthesis of [¹⁸F]MH.MZ via direct radiofluorination. Unfortunately, the direct radiofluorination did not have any significant benefits over the indirect labelling method. This is mainly because the precursor for the direct labelling approach is not completely stable and slowly decomposes. However, only one HPLC separation is necessary for the direct ¹⁸F‐nucleophilic labelling procedure, and accordingly, automation is easier. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis of [18F]‐6‐deoxy‐6‐fluoro‐D‐glucose ([18F]6FDG), a potential tracer of glucose transport

With the goal of developing a PET radioligand for the in vivo assessment of glucose transport, 6-deoxy-6-[¹⁸F]fluoro-D -glucose ([¹⁸F]6FDG) was prepared in two steps from ¹⁸F⁻. Starting with D -glucose, the tosyl- and mesyl-derivatives of 3,5-O-benzylidene-1,2-O-isopropylidene-α-D -glucofuranose were prepared by known methods. Reaction of either of these precursors with ¹⁸F⁻ resulted in the formation of 3,5-O-benzylidene-6-deoxy-6-[¹⁸F]-fluoro-1,2-O-isopropylidene-α-D -glucofuranose in high yield. Subsequent hydrolysis resulted in the production of [¹⁸F]6FDG. Under optimal conditions, [¹⁸F]6FDG is produced 60–70 min after end of bombardment (EOB) in 71 ± 12% yield (decay corrected, based upon fluoride) with a radiochemical purity of ⩾96%. Preliminary experiments have indicated that [¹⁸F]6FDG may be a more representative in vivo tracer for the glucose transporter than 2FDG. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of a [18F]fluorobenzothiazole as potential amyloid imaging agent

This study describes the synthesis of a fluoroethylated derivative of [N‐methyl‐¹¹C]2‐(4′‐methylaminophenyl)‐6‐hydroxybenzothiazole ([¹¹C]6‐OH‐BTA‐1; Pittsburgh Compound B (PIB)), an already established amyloid imaging agent. The [¹¹C]methylamino group of [¹¹C]6‐OH‐BTA‐1 was formally replaced by a fluoroethyl group in a cold synthesis via N‐alkylation of N‐Boc‐2‐(4′‐aminophenyl)‐6‐(methoxyethoxymethoxy)benzothiazole with fluoroethyl tosylate. Subsequent deprotection gave the target compound 2‐[4′‐(2‐fluoroethyl)aminophenyl]‐6‐hydroxybenzothiazole (FBTA). In a radioligand competition assay on aggregated synthetic amyloid fibrils using N‐[³H‐methyl]6‐OH‐BTA‐1, 100 nM FBTA inhibited binding with 93 ± 1 and 83 ± 1% efficiency for Aβ_1–40 and Aβ_1–42, respectively. For the radiosynthesis a precursor carrying a tosylethyl moiety was prepared allowing the introduction of [¹⁸F]fluoride via nucleophilic substitution with [¹⁸F]tetra‐n‐butyl‐ammonium fluoride (TBAF). Subsequent removal of all protecting groups was performed in a one‐pot procedure followed by semi‐preparative HPLC, delivering the target compound [¹⁸F]FBTA in good radiochemical yield of 21% on average and radiochemical purity of ?98% at EOS. In vitro autoradiography on human postmortem AD brain tissue slices showed intense cortical binding of [¹⁸F]FBTA (1 nM), which was displaced in presence of 6‐OH‐BTA‐1 (1 µM). Brain up‐take was evaluated in wild‐type (wt) mice with microPET imaging. Based on these results, [¹⁸F]FBTA appears to be a suitable candidate tracer for amyloid imaging in humans. Copyright © 2008 John Wiley & Sons, Ltd.     

Efficient automated syntheses of high specific activity 6‐[18F]fluorodopamine using a diaryliodonium salt precursor

6‐[¹⁸F]Fluorodopamine (6‐[¹⁸F]F‐DA) is a positron emission tomography radiopharmaceutical used to image sympathetic cardiac innervation and neuroendocrine tumors. Imaging with 6‐[¹⁸F]F‐DA is constrained, in part, by the bioactivity and neurotoxicity of 6‐[¹⁹F]fluorodopamine. Furthermore, routine access to this radiotracer is limited by the inherent difficulty of incorporation of [¹⁸F]fluoride into electron‐rich aromatic substrates. We describe the simple and direct preparation of high specific activity (SA) 6‐[¹⁸F]F‐DA from no‐carrier‐added (n.c.a.) [¹⁸F]fluoride. Incorporation of n.c.a. [¹⁸F]fluoride into a diaryliodonium salt precursor was achieved in 50–75% radiochemical yields (decay corrected to end of bombardment). Synthesis of 6‐[¹⁸F]F‐DA on the IBA Synthera® and GE TRACERlab FX‐FN automated platforms gave 6‐[¹⁸F]F‐DA in >99% chemical and radiochemical purities after HPLC purification. The final non‐corrected yields of 6‐[¹⁸F]F‐DA were 25 ± 4% (n = 4, 65 min) and 31 ± 6% (n = 3, 75 min) using the Synthera and TRACERlab modules, respectively. Efficient access to high SA 6‐[¹⁸F]F‐DA from a diaryliodonium salt precursor and n.c.a. [¹⁸F]fluoride is provided by a relatively subtle change in reaction conditions – replacement of a polar aprotic solvent (acetonitrile) with a relatively nonpolar solvent (toluene) during the critical radiofluorination reaction. Implementation of this process on common radiochemistry platforms should make 6‐[¹⁸F]F‐DA readily available to the wider imaging community.     

The synthesis of a new probe for PET imaging reporter gene HSV1‐tk: 2‐amino‐6‐[18F] fluoro‐9‐ (4‐hydroxy‐3‐hydroxymethylbutyl) purine (6‐[18F]fluoropenciclovir)

The one step radiosynthesis of 2‐amino‐6‐ [¹⁸F]fluoro‐9‐(4‐hydroxy‐3‐hydroxymethylbutyl) purine (6‐[¹⁸F]fluoropenciclovir) 6 is reported. Radiolabeled product 6‐[¹⁸F]fluoropenciclovir 6 was prepared by radiofluorination of compound 4 with [¹⁸F]KF and isolated by a silica Sep‐Pak cartridge. The radiochemical yield of compound 6 was 45–55% decay corrected (d.c.) in six runs with radiochemical purity >98% and the radiosynthesis time was 35–42 min from end of bombardment (EOB). Copyright © 2006 John Wiley & Sons, Ltd.     

[18F]Fluoropyridine-losartan: A new approach toward human Positron Emission Tomography imaging of Angiotensin II Type 1 receptors

Angiotensin II type 1 receptors (AT₁R) blocker losartan is used in patients with renal and cardiovascular diseases. [¹⁸F]fluoropyridine-losartan has shown favorable binding profile for quantitative renal PET imaging of AT₁R with selective binding in rats and pigs, low interference of radiometabolites and appropriate dosimetry for clinical translation. A new approach was developed to produce [¹⁸F]fluoropyridine-losartan in very high molar activity. Automated radiosynthesis was performed in a three-step, two-pot, and two-HPLC-purification procedure within 2 h. Pure [¹⁸F]FPyKYNE was obtained by radiofluorination of NO₂PyKYNE and silica-gel-HPLC purification (40 ± 9%), preventing the formation of nitropyridine-losartan in the second step. Conjugation with trityl-losartan azide via click chemistry, followed by acid hydrolysis, C18-HPLC purification and reformulation provided [¹⁸F]fluoropyridine-losartan in 11 ± 2% (decay-corrected from [¹⁸F]fluoride, EOB). Using tris[(1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methyl]-amine (THPTA) as a Cu(I)-stabilizing agent for coupling [¹⁸F]FPyKYNE to the unprotected losartan azide afforded [¹⁸F]fluoropyridine-losartan in similar yields (11 ± 3%, decay-corrected from [¹⁸F]fluoride, EOB). Reverse-phase HPLC was optimized by reducing the pH of the mobile phase to achieve complete purification and high molar activities (467 ± 60 GBq/μmol). The use of radioprotectants prevented tracer radiolysis for 10 h (RCP > 99%). The product passed the quality control testing. This reproducible automated radiosynthesis process will allow in vivo PET imaging of AT₁R expression in several diseases.     

An improved preparation of [18F]AV-45 by simplified solid-phase extraction purification

Amyvid (florbetapir f18, [¹⁸F]AV-45, [¹⁸F] 5 ) was the first FDA-approved positron emission tomography imaging agent targeting β-amyloid (Aβ) plaques for assisting the diagnosis of Alzheimer disease. This work aimed to improve the [¹⁸F]AV-45 ([¹⁸F] 5 ) preparation by using solid-phase extraction (SPE) purification. [¹⁸F]AV-45 ([¹⁸F] 5 ) was synthesized by direct nucleophilic radiofluorination of O-tosylated precursor (1 mg) at 120°C in anhydrous dimethyl sulfoxide (DMSO), followed by acid hydrolysis of the N-Boc protecting group. Purification was accomplished by loading the crude reaction mixture to a cartridge (Oasis HLB 3 cc) and eluting with different combinations of solvents. This method removed the chemical impurity while leaving [¹⁸F]AV-45 ([¹⁸F] 5 ) on the cartridge. The final dose was eluted by ethanol. [¹⁸F]AV-45 ([¹⁸F] 5 ) was produced within 51 minutes (radiochemical yield 42.7 ± 5.9%, decay corrected, n = 3), and the radiochemical purity was greater than 95%. Total chemical impurity per batch (24.1 ± 2.7 μg per batch) was below the limit described in the package insert of Amyvid, florbetapir f18 (chemical mass: less than 50 μg/dose). In summary, [¹⁸F]AV-45 ([¹⁸F] 5 ) was produced efficiently and reproducibly using a cartridge-based SPE purification. This method brings the process closer for routine preparation, similar to the commercially used [¹⁸F]FDG.     

Radiosynthesis of [18F]ATPFU: a potential PET ligand for mTOR

Mammalian target of rapamycin (mTOR) plays a pivotal role in many aspects of cellular proliferation, and recent evidence suggests that an altered mTOR signaling pathway plays a central role in the pathogenesis of aging, tumor progression, neuropsychiatric, and major depressive disorder. Availability of a mTOR‐specific PET tracer will facilitate monitoring early response to treatment with mTOR inhibitors that are under clinical development. Towards this we have developed the radiosynthesis of [¹⁸F]1‐(4‐(4‐(8‐oxa‐3‐azabicyclo[3.2.1]octan‐3‐yl)‐1‐(2,2,2‐trifluoroethyl)‐1H‐pyrazolo[3,4‐d]pyrimidin‐6‐yl)phenyl)‐3‐(2‐fluoroethyl)urea [¹⁸F]ATPFU ([¹⁸F]1) as an mTOR PET ligand. Synthesis of reference 1 and the precursor for radiolabeling, 4‐(4‐8‐oxa‐3‐azabicyclo[3.2.1]‐octan‐3yl)‐1‐(2,2,2‐trifluoroethyl)‐1H‐pyrazolo[3,4‐d]pyrimidin‐6yl)aniline (10), were achieved from beta‐chloroaldehyde 3 in 4 and 5 steps, respectively, with an overall yield of 25–28%. [¹⁸F]Fluoroethylamine was prepared by heating N‐[2‐(toluene‐4‐sulfonyloxy)ethyl]phthalimide with [¹⁸F]fluoride ion in acetonitrile. [¹⁸F]1 was obtained by slow distillation under argon of [¹⁸F]FCH₂CH₂NH₂ into amine 10 that was pre‐treated with triphosgene at 0–5 °C. The total time required for the two‐step radiosynthesis including semi‐preparative HPLC purification was 90 min, and the overall radiochemical yield of [¹⁸F]1 for the process was 15 ± 5% based on [¹⁸F]fluoride ion (decay corrected). At the end of synthesis (EOS), the specific activity was 37–74 GBq/µmol (N = 6).     

Radiosynthesis of the norepinephrine transporter tracer [18F]NS12137 via copper‐mediated 18F‐labelling

[¹⁸F]NS12137 (exo‐3‐[(6‐[¹⁸F]fluoro‐2‐pyridyl)oxy]8‐azabicyclo[3.2.1]octane) is a highly selective norepinephrine transporter (NET) tracer. NETs are responsible for the reuptake of norepinephrine and dopamine and are linked to several neurodegenerative and neuropsychiatric disorders. The aim of this study was to develop a copper‐mediated ¹⁸F‐fluorination method for the production of [¹⁸F]NS12137 with straightforward synthesis conditions and high radiochemical yield and molar activity. [¹⁸F]NS12137 was produced in two steps. Radiofluorination of [¹⁸F]NS12137 was performed via a copper‐mediated pathway starting with a stannane precursor and using [¹⁸F]F^? as the source of the fluorine‐18 isotope. Deprotection was performed via acid hydrolysis. The radiofluorination reaction was nearly quantitative as was the deprotection based on HPLC analysis. The radiochemical yield of the synthesis was 15.1 ± 0.5%. Molar activity of [¹⁸F]NS12137 was up to 300 GBq/μmol. The synthesis procedure is straightforward and can easily be automated and adapted for clinical production.     

A concisely automated synthesis of TSPO radiotracer [18F]FDPA based on spirocyclic iodonium ylide method and validation for human use

Fluorine-18 labeled N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ([¹⁸F]FDPA) is a potent and selective radiotracer for positron-emission tomography (PET) imaging of the translocator protein 18 kDa (TSPO). Our previous in vitro and in vivo evaluations have proven that this tracer is promising for further human translation. Our study addresses the need to streamline the automatic synthesis of this radiotracer to make it more accessible for widespread clinical evaluation and application. Here, we successfully demonstrate a one-step radiolabeling of [¹⁸F]FDPA based on a novel spirocyclic iodonium ylide (SCIDY) precursor using tetra-n-butyl ammonium methanesulfonate (TBAOMs), which has demonstrated the highest radiochemical yields and molar activity from readily available [¹⁸F]fluoride ion. The nucleophilic radiofluorination was completed on a GE TRACERlab FX2 N synthesis module, and the formulated [¹⁸F]FDPA was obtained in nondecay corrected (n.d.c) radiochemical yields of 15.6 ± 4.2%, with molar activities of 529.2 ± 22.5 GBq/μmol (14.3 ± 0.6 Ci/μmol) at the end of synthesis (60 minutes, n = 3) and validated for human use. This methodology facilitates efficient synthesis of [¹⁸F]FDPA in a commercially available synthesis module, which would be broadly applicable for routine production and widespread clinical PET imaging studies.