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 [18F]fluoroalkyl esters of carfentanil

With the aim to develop and evaluate new ligands for depicting the µ‐opioid receptor with positron emission tomography, the ¹⁸F‐fluoroalkyl esters of carfentanil, 3‐carboxy‐(2‐[¹⁸F]fluoroethyl)fentanyl, (2‐[¹⁸F]fluoroethyl‐carfentanil) and 3‐carboxy‐(3‐[¹⁸F]fluoropropyl)fentanyl (3‐[¹⁸F]fluoropropyl‐carfentanil) were prepared by a two‐step radiosynthesis. Reacting carfentanil carboxylate sodium salt, added 0.96 eqv. of tetrabutyl ammonium hydroxide (TBAH), with no‐carrier‐added (n.c.a.) 2‐[¹⁸F]fluoroethyltosylate for 20 min at 150°C in dimethyl formamide (DMF) provided 2‐[¹⁸F]fluoroethyl carfentanil in an isolated radiochemical yield (RCY) of 36 ± 8%, a specific activity (S_A) of 35 ± 5 TBq/mmol (n=4) within a synthesis time of ～100 min. Similarly, 3‐[¹⁸F]fluoropropyl carfentanil could be obtained by reacting the carfentanil TBA/Na salt with 3‐[¹⁸F]fluoropropyl iodide at 160°C in DMF (isolated RCY=6 ± 2%; ～100 min, S_A=27 ± 5 TBq/mmol, n=4). The developed methods allow the production of the two ¹⁸F‐labeled carfentanil derivatives in amounts and specific activities necessary and relevant for a detailed preclinical evaluation of these new potential µ‐opioid receptor ligands in vitro and in animal models. Copyright © 2005 John Wiley & Sons, Ltd.     

Substitution‐reduction: an alternative process for the [18F]N‐(2‐fluoroethylation) of anilines

Substitution of a halo atom (chloro or bromo) in easily prepared N‐haloacetyl‐anilines with no‐carrier added (NCA) cyclotron‐produced [¹⁸F]fluoride ion (¹⁸F, t_1/2= 109.8 min; β⁺=96.9%), followed by reduction with borane–tetrahydrofuran (BH₃–THF), provides an alternative route to NCA [¹⁸F]N‐(2‐fluoroethyl)‐anilines. This two‐step and one‐pot process is rapid (～50 min) and moderately high yielding (～40% decay‐corrected radiochemical yield (RCY) overall). In the nucleophilic substitution reaction, 18‐crown‐6 is preferred to Kryptofix^® 222 as complexing agent for the solubilization of the counter‐ion (K⁺), derived from an added metal salt, in acetonitrile. Weakly basic potassium bicarbonate is preferred as the added metal salt. Inclusion of a small amount of water, equating to 4–5 molar equivalents relative to 18‐crown‐6, base or precursor (held in equimolar ratio), is beneficial in preventing the adsorption of radioactivity onto the wall of the glass reaction vessel and for achieving high RCY in the nucleophilic substitution reaction. BH₃–THF is effective for the rapid reduction of the generated [¹⁸F]N‐fluoroacetyl‐aniline to the [¹⁸F]N‐(2‐fluoroethyl)‐aniline. Copyright © 2004 John Wiley & Sons, Ltd.     

Baeyer‐Villiger oxidation tuned to chemoselective conversion of non‐activated [18F]fluorobenzaldehydes to [18F]fluorophenols

A reaction pathway via oxidation of [¹⁸F]fluorobenzaldehydes offers a very useful tool for the no‐carrier‐added radiosynthesis of [¹⁸F]fluorophenols, a structural motive of several potential radiopharmaceuticals. A considerably improved chemoselectivity of the Baeyer‐Villiger oxidation (BVO) towards phenols was achieved, employing 2,2,2‐trifluoroethanol as reaction solvent in combination with Oxone or m‐CPBA as oxidation agent. The studies showed the necessity of H₂SO₄ addition, which appears to have a dual effect, acting as catalyst and desiccant. For example, 2‐[¹⁸F]fluorophenol was obtained with a RCY of 97% under optimised conditions of 80°C and 30‐minute reaction time. The changed performance of the BVO, which is in agreement with known reaction mechanisms via Criegee intermediates, provided the best results with regard to radiochemical yield (RCY) and chemoselectivity, i.e. formation of [¹⁸F]fluorophenols rather than [¹⁸F]fluorobenzoic acids. Thus, after a long history of the BVO, the new modification now allows an almost specific formation of phenols, even from electron‐deficient benzaldehydes. Further, the applicability of the tuned, chemoselective BVO to the n.c.a. level and to more complex compounds was demonstrated for the products n.c.a. 4‐[¹⁸F]fluorophenol (RCY 95%; relating to 4‐[¹⁸F]fluorobenzaldehyde) and 4‐[¹⁸F]fluoro‐m‐tyramine (RCY 32%; relating to [¹⁸F]fluoride), respectively.     

Copper‐mediated reduction of 2‐[18F]fluoroethyl azide to 2‐[18F]fluoroethylamine

¹⁸F‐labelled fluoroalkylamines are attractive reagents for the preparation of positron emission tomography tracers containing amine, amide, and N‐heterocyclic moieties. Herein, we report that 2‐[¹⁸F]fluoroethylamine can be obtained from 2‐[¹⁸F]fluoroethyl azide by reduction with elemental copper under acidic conditions. Azide to amine reduction was achieved in near quantitative analytical yields within 30 min by heating a solution of 2‐[¹⁸F]fluoroethyl azide in the presence of copper wire and aqueous trifluoroacetic acid. Subsequent reaction of 2‐[¹⁸F]fluoroethylamine with benzoyl chloride in the presence of triethylamine provided N‐[¹⁸F]fluoroethyl benzamide in 63% decay‐corrected radiochemical yield from 2‐[¹⁸F]fluoroethyl azide. The utility of the Cu(0)/H⁺ azide reduction method was further exemplified by preparation of the potential GABA_A tracer 9H‐β‐carboline N‐2‐[¹⁸F]fluoroethylamide, which was obtained in 46% decay‐corrected radiochemical yield by reaction of 2‐[¹⁸F]fluoroethylamine with the corresponding 9H‐β‐carboline pentafluorophenyl ester. Copyright © 2012 John Wiley & Sons, Ltd.     

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.     

C‐Terminal 18F‐fluoroethylamidation exemplified on [Gly‐OH9] oxytocin

The no‐carrier‐added (n.c.a.) ¹⁸F‐fluoroethylamidation of the acid function of the protected nonapeptide Boc–Cys–Tyr(tBu)–Ile–Gln(Mtt)–Asn(Mtt)–Cys–Pro–Leu–Gly–OH forming the labelled peptide hormone derivative [Gly‐(2‐[¹⁸F]fluoroethyl)NH⁹]‐oxytocin is described. The labelling conditions were elaborated using a protected tripeptide, identical to the C‐terminal sequence of oxytocin. The prosthetic group n.c.a. 2‐[¹⁸F]fluoroethylamine was synthesised via cryptate mediated n.c.a. ¹⁸F‐fluorination of N‐Boc‐2‐(p‐toluenesulfonyloxy)ethylamine in DMSO (RCY: ca. 60%) and subsequent deprotection with a radiochemical yield of 46±5%. [¹⁸F]Fluoroethylamine was reacted with Z–Pro–Leu–Gly–OH in presence of the coupling reagent TBTU or with activated esters of the model‐tripeptide. The activated ester method as well as the condensation in presence of TBTU yielded ?90% of the ¹⁸F‐fluoroethyl‐amidated tripeptide. TBTU‐mediated condensation of n.c.a. 2‐[¹⁸F]fluoro‐ethylamine with the C‐terminal free acid group of protected oxytocin gave the radiochemical yield of about 75%. Deprotection under acidic conditions led to the formation of [Gly–(2‐[¹⁸F]fluoroethyl)NH⁹]oxytocin within 75 min with a radiochemical yield of about 30% as measured by analytical HPLC. Copyright © 2002 John Wiley & Sons, Ltd.     

Optimization of the preparation of fluorine‐18‐labeled steroid receptor ligands 16alpha‐[18F]fluoroestradiol (FES), [18F]fluoro furanyl norprogesterone (FFNP), and 16beta‐[18F]fluoro‐5alpha‐dihydrotestosterone (FDHT) as radiopharmaceuticals

Fluorine‐18‐labeled steroid receptor tracers, 16α‐[¹⁸F]fluoroestradiol (FES), [¹⁸F]fluoro furanyl norprogesterone (FFNP), and 16β‐[¹⁸F]fluoro‐5α‐dihydrotestosterone (FDHT), are important imaging tools for studies of breast and prostate cancers using positron emission tomography (PET). The automated production of these ligands with high specific activity (SA) as radiopharmaceuticals requires modification and optimization of the currently reported methods. [¹⁸F]FES with high SA was synthesized in over 60% radiochemical yield (RCY) at the end of synthesis (EOS) using a small amount of precursor (1) (as low as 0.3 mg) and 1 M H₂SO₄ for deprotection of the intermediate (2). [¹⁸F]FFNP was synthesized in up to 77% RCY at EOS using the triflate precursor (4) at room temperature or in 25% RCY using the mesylate precursor (6) at 65°C. Both methods are highly reproducible and afford high SA. [¹⁸F]FDHT was synthesized by radiofluoride incorporation at room temperature, reduction with NaBH₄, and deprotection with HCl/acetone, giving [¹⁸F]FDHT in up to 75% yield (RCY). All of these methods can be easily translated to automated production. The information provided here will aid in the development of automated production of these steroid receptor tracers with high or improved yields, optimal SA, and ease of processing for research and clinical use. Copyright © 2014 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.     

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.     

Radiosynthesis of 1′‐[18F]fluoroethyl‐β‐D‐lactose ([18F]‐FEL) for early detection of pancreatic carcinomas with PET

Introduction: The hepatocellular carcinoma–intestine–pancreas and pancreatitis‐associated proteins, also known as lactose‐binding protein, is upregulated in peritumoral pancreatic tissue. Previously, we reported ethyl‐ β ‐D ‐galactopyranosyl‐(1,4′)‐2′‐deoxy‐2′‐[¹⁸F]fluoro‐ β ‐D ‐glucopyranoside (Et‐[¹⁸F]‐FDL), a radiofluorinated lactose analog for positron emission tomography (PET) of small pancreatic carcinomas in mice. However, synthesis of the precursor for Et‐[¹⁸F]‐FDL involves 11 steps, which is quite lengthy, and produces overall low yields. Here, we report on synthesis and radiolabeling of another analog of lactose, the 1′‐[¹⁸F]fluoroethyl‐ β ‐D ‐lactose for PET imaging of pancreatic carcinomas. Methods: Two precursor compounds, 1′‐bromoethyl‐2′,3′,6′,2,3,4,6‐hepta‐O‐acetyl‐ β ‐D ‐lactose 4, and 1′‐p‐toluenesulfonylethyl‐2′,3′,6′,2,3,4,6‐hepta‐O‐acetyl‐ β ‐D ‐lactose 5, were synthesized in two and three steps, respectively; then, cold fluorination and radiofluorination of these precursors were performed. The reaction mixture was passed through a silica gel Sep‐pack cartridge, eluted with EtOAc, and the 1′‐[¹⁸F]fluoroethyl‐2′,3′,6′,2,3,4,6‐hepta‐O‐acetyl‐ β ‐D ‐lactose ([¹⁸F]‐6) purified by HPLC. After hydrolysis of the protecting groups, the 1′‐[¹⁸F]fluoroethyl‐ β ‐D ‐lactose [¹⁸F]‐7 was neutralized, diluted with saline, filtered through a sterile Millipore filter, and analyzed by radio‐TLC. Results: The average decay‐corrected radiochemical yield was 9% (n = 7) with>99% radiochemical purity and specific activity of 55.5 GBq/ µ mol. Conclusion : A new analog of lactose, 1′‐[¹⁸F]fluoroethyl‐ β ‐D ‐lactose, has been synthesized in good yields, with high purity and high specific activity suitable for PET imaging of early pancreatic carcinomas. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis and radiosynthesis of N5‐[18F]fluoroethyl‐Pirenzepine and its metabolite N5‐[18F]fluoroethyl‐LS 75

The well established M₁ selective muscarinergic antagonist Pirenzepine 11‐[2‐(4‐methyl‐piperazin‐1‐yl)‐acetyl]‐5,11‐dihydro‐benzo[e]pyrido[3,2‐b][1,4]diazepin‐6‐one (1) exhibits an unusual behaviour in vivo, which cannot be explained with M₁ antagonism exclusively. One of the aspects discussed is a specific interaction with poly ADP‐ribose polymerase (PARP‐1). 1 undergoes metabolism to form LS 75 5,11‐dihydro‐benzo[e]pyrido[3,2‐b][1,4]diazepin‐6‐one (2). In order to study deviations in Pirenzepine efficacy from pure M₁ binding in vivo using PET, appropriate positron emitter labelled analogues of 1 and 2 were synthesised. Non‐radioactive reference compounds 3 and 4 were tested for PARP‐1 inhibition. The n‐octanol–water partition coefficients of compounds 1, 2, 3 and 4 at pH 7.4 (logD_7.4) were determined. Both, 3 and 4 were labelled with ¹⁸F via 2‐[¹⁸F]fluoroalkylation in position 5 of the benzodiazepinone moiety to obtain N⁵‐[¹⁸F]fluoroethyl Pirenzepine [¹⁸F]‐3 and N⁵‐[¹⁸F]fluoroethyl LS 75 [¹⁸F]‐4. Radiotracers [¹⁸F]‐3 and [¹⁸F]‐4 were obtained in radiochemical yields of 15±4 % and 30±5% after 120 and 110 min, respectively. Metabolism of both compounds was investigated in vitro in human and rat plasma, respectively. Compound 3 did not show activity as an inhibitor of PARP‐1. Contrary, 4 displays moderate PARP‐1 inhibition potency. The new radiotracer [¹⁸F]‐4 can be applied for molecular imaging using autoradiography and PET. Copyright © 2009 John Wiley & Sons, Ltd.     

Radiosynthesis and in vivo study of [18F]1‐(2‐fluoroethyl)‐4‐[(4‐cyanophenoxy)methyl]piperidine: a promising new sigma‐1 receptor ligand

The novel sigma‐1 receptor PET radiotracer [¹⁸F]1‐(2‐fluoroethyl)‐4‐[(4‐cyanophenoxy)methyl]piperidine ([¹⁸F]WLS1.002, [¹⁸F]‐2) was synthesized (n=6) by heating the corresponding N‐ethylmesylate precursor in an anhydrous acetonitrile solution containing [¹⁸F]fluoride, Kryptofix K₂₂₂ and potassium carbonate for 15 min. Purification was accomplished by reverse‐phase HPLC methods, providing [¹⁸F]‐2 in 59±8% radiochemical yield (EOB), with specific activity of 2.89±0.80 Ci/µmol (EOS) and radiochemical purity of 98.3±2.1%. Rat biodistribution studies revealed relatively high uptake in many organs known to contain sigma‐1 receptors, including the lungs, kidney, heart, spleen, and brain. Good clearance from normal tissues was observed over time. Blocking studies (60 min) demonstrated high (>80%) specific binding of [¹⁸F]‐2 in the brain, with reduction also noted in other organs known to express these sites. Copyright © 2005 John Wiley & Sons, Ltd.     

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).     

Synthesis and bioevaluation of 4‐chloro‐2‐tert‐butyl‐5‐[2‐[[1‐[2‐[18F]fluroethyl]‐1H‐1,2,3‐triazol‐4‐yl]methyl]phenylmethoxy]‐3(2H)‐pyridazinone as potential myocardial perfusion imaging agent with PET

This study reports the synthesis and characterization of 4‐chloro‐2‐tert‐butyl‐5‐[2‐[[1‐[2‐[¹⁸F]fluroethyl]‐1H‐1,2,3‐triazol‐4‐yl]methyl]phenylmethoxy]‐3(2H)‐pyridazinone ([¹⁸F]Fmp2) for myocardial perfusion imaging (MPI). The tosylate precursor and non‐radioactive compound [¹⁹F]Fmp2 were synthesized and characterized by infrared, ¹H‐NMR, ¹³C‐NMR, and mass spectra (MS). The radiotracer [¹⁸F]Fmp2 was obtained by one‐step nucleophilic substitution of tosyl with ¹⁸F, and evaluated as an MPI agent in vitro and in vivo. Starting from [¹⁸F]KF/K₂₂₂ solution, the typical decay‐corrected radiochemical yield (RCY) was 38 ± 8.8% with high radiochemical purity (>98%). The specific activity was calculated as 10 GBq/µmol at the end of synthesis determined by HPLC analysis. In the mice biodistribution, [¹⁸F]Fmp2 showed very high initial heart uptake (53.35 ± 5.47 %ID/g at 2 min after injection) and remarkable retention. The heart/liver, heart/lung, and heart/blood ratios were 7.98, 8.20, and 53.13, respectively at 2 min post‐injection. In the Positron Emission Tomography (PET) imaging study of Chinese mini‐swine, the standardized uptake value of the liver decreased modestly during the 2 h post‐injection, while the heart uptake and heart/liver ratios continued to increase with time. [¹⁸F]Fmp2 exhibited good stability, high heart uptake and low lung uptake in mice and Chinese mini‐swine. It may be worthy of further modification to improve liver clearance for MPI in the future.     

Automated synthesis of 18F‐labelled analogs of metomidate,vorozole and harmine using commercial platform

Three ¹⁸F‐labelled PET tracers, 2‐[¹⁸F]fluoroethyl 1‐[(1R)‐1‐phenylethyl]‐1H‐imidazole‐5‐carboxylate ([¹⁸F]FETO), 6‐[(S)‐(4‐chlorophenyl)‐(1H)‐1,2,4‐triazol‐1‐yl)methyl]‐1‐(2‐[¹⁸F]fluoroethyl)‐1H‐benzotriazole ([¹⁸F]FVOZ) and 7‐[2‐(2‐[¹⁸F]fluoroethoxy)ethoxy]‐1‐9H‐ β ‐carboline ([¹⁸F]FHAR) were synthesized by a one‐step nucleophilic fluorination using the automated commercial platform TRACERLab FX_FN. The labelled products were obtained with 16–20% isolated decay corrected radiochemical yields after 70–75 min synthesis time. The radiochemical and chemical purities were more than 98% in all cases. The synthesis using commercial platform may make these tracers more accessible for clinical research. Copyright © 2010 John Wiley & Sons, Ltd.     

Automation of [18F]fluoroacetaldehyde synthesis: application to a recombinant human interleukin‐1 receptor antagonist (rhIL‐1RA)

[¹⁸F]Fluoroacetaldehyde is a biocompatible prosthetic group that has been implemented pre‐clinically using a semi‐automated remotely controlled system. Automation of radiosyntheses permits use of higher levels of [¹⁸F]fluoride whilst minimising radiochemist exposure and enhancing reproducibility. In order to achieve full‐automation of [¹⁸F]fluoroacetaldehyde peptide radiolabelling, a customised GE Tracerlab FX‐FN with fully programmed automated synthesis was developed. The automated synthesis of [¹⁸F]fluoroacetaldehyde is carried out using a commercially available precursor, with reproducible yields of 26% ± 3 (decay‐corrected, n = 10) within 45 min. Fully automated radiolabelling of a protein, recombinant human interleukin‐1 receptor antagonist (rhIL‐1RA), with [¹⁸F]fluoroacetaldehyde was achieved within 2 h. Radiolabelling efficiency of rhIL‐1RA with [¹⁸F]fluoroacetaldehyde was confirmed using HPLC and reached 20% ± 10 (n = 5). Overall RCY of [¹⁸F]rhIL‐1RA was 5% ± 2 (decay‐corrected, n = 5) within 2 h starting from 35 to 40 GBq of [¹⁸F]fluoride. Specific activity measurements of 8.11–13.5 GBq/µmol were attained (n = 5), a near three‐fold improvement of those achieved using the semi‐automated approach. The strategy can be applied to radiolabelling a range of peptides and proteins with [¹⁸F]fluoroacetaldehyde analogous to other aldehyde‐bearing prosthetic groups, yet automation of the method provides reproducibility thereby aiding translation to Good Manufacturing Practice manufacture and the transformation from pre‐clinical to clinical production.     

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.     

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 O‐ and N‐(β‐fluoroethylation)s with NCA [18F]β‐fluoroethyl tosylate under microwave‐enhanced conditions

Reactions of no‐carrier‐added (NCA) [¹⁸F]β‐fluoroethyl tosylate with amine, phenol or carboxylic acid to form the corresponding [¹⁸F]N‐(β‐fluoroethyl)amine, [¹⁸F]β‐fluoroethyl ether or [¹⁸F]β‐fluoroethyl ester, were found to be rapid (2–10 min) and efficient (51–89% conversion) under microwave‐enhanced conditions. These conditions allow reactants to be heated rapidly to 150°C in a low boiling point solvent, such as acetonitrile, and avoid the need to use high boiling point solvents, such as DMSO and DMF, to promote reaction. The microwave‐enhanced reactions gave about 20% greater radiochemical yields than thermal reactions performed at similar temperatures and over similar reaction times. With a bi‐functional molecule, such as DL‐pipecolinic acid, [¹⁸F]β‐fluoroethyl tosylate reacts exclusively with the amino group. Copyright © 2004 John Wiley & Sons, Ltd.