One‐step radiosynthesis of 4‐[18F]flouro‐3‐nitro‐N‐2‐propyn‐1‐yl‐benzamide ([18F]FNPB): a new stable aromatic porosthetic group for efficient labeling of peptides with fluorine‐18

4‐[¹⁸F]flouro‐3‐nitro‐N‐2‐propyn‐1‐yl‐benzamide ([¹⁸F]FNPB) was developed as a new stable aromatic prosthetic group for more efficient click labeling of peptides. A new aromatic precursor 3,4‐dinitro‐N‐2‐propyn‐1‐yl‐benzamide was radiofluorinated using [¹⁸F]KF/K2.2.2 followed by HPLC purification to obtain the desired product [¹⁸F]FNPB. [¹⁸F]FNPB was synthesized with a 58% radiochemical yield, a specific activity > 350 GBq/µmol, and radiochemical purity was exceeded 98% in 40 min. The in vitro stability studies showed no detectable radiodefluorination over 2 h in mouse plasma. The click labeling yield of three different peptides with [¹⁸F]FNPB were all above 87%. The in vitro study suggests that [¹⁸F]FNPB may be stable in vivo and could have general application in labeling peptides with high radiochemical yield for positron emission tomography applications. Copyright © 2012 John Wiley & Sons, Ltd.     

Development of 6‐[18F]fluoro‐carbohydrate‐based prosthetic groups and their conjugation to peptides via click chemistry

This work describes the development of new 6‐[¹⁸F]fluoro‐carbohydrate‐based prosthetic groups equipped with an azido arm that are able to participate in copper(I)‐catalyzed cycloadditions for ¹⁸F labeling of biomolecules under mild conditions. The radiolabeling in high radiochemical yields (up to 68 ± 6%) of these different prosthetic groups is presented. The flexibility of the azido arm introduced on the carbohydrate moieties allows efficient click reactions with different alkyne functionalized peptides such as gluthation or Arg‐Gly‐Asp derivatives in order to prepare glycopeptides. The radiosyntheses of ¹⁸F‐labeled glycopeptides proceed in high radiochemical yields (up to 76%) in an automated process with excellent radiochemical purity. The addition of a sugar moiety on peptides should enhance the bioavailability, pharmacokinetic, and in vivo clearance properties of these glycopeptides, compared with the unlabeled native peptide, and these properties are highly favorable for positron emission tomography imaging. A high uptake of ¹⁸F‐β‐gluco‐c(RGDfC) is shown by positron emission tomography imaging in a subcutaneous abscess model in the rat, revealing the potential of this tracer to monitor integrin expression as a part of inflammation and/or angiogenesis processes.     

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.     

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.     

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.     

Fluorine‐18 labelling of small interfering RNAs (siRNAs) for PET imaging

Small interfering RNAs (siRNAs), a class of macromolecules constituted by the association of two single‐stranded ribonucleic acids of short sequences, have been labelled with the positron‐emitter fluorine‐18 (T_1/2: 109.8 min). The strategy involves (1) prosthetic conjugation of a single‐stranded oligonucleotide with [¹⁸F]FPyBrA (N‐[3‐(2‐[¹⁸F]fluoropyridin‐3‐yloxy)‐propyl]‐2‐bromoacetamide) followed by (2) formation of the target duplex by annealing with the complementary sequence, therefore, permitting parallel and combinatorial preparation of [¹⁸F]siRNAs. Pure fluorine‐18‐labelled siRNAs (0.55–1.11 GBq, specific activity: 74–148 GBq/µmol at EOB) could be obtained within 165 min starting from 37.0 GBq of starting [¹⁸F]fluoride (1.5–3.0%, non‐decay‐corrected isolated yields). Copyright © 2007 John Wiley & Sons, Ltd.     

Fluorine‐18 labelling of a series of potential EGFRvIII targeting peptides with a parallel labelling approach using [18F]FPyME

There is growing interest in the use of radiolabelled peptides as receptor targeting agents for diagnostic imaging of various cancer types using positron emission tomography. In this work, 1‐[3‐(2‐[¹⁸F]fluoropyridin‐3‐yloxy)propyl]pyrrole‐2,5‐dione ([¹⁸F]FPyME) has been used for parallel fluorine‐18 labelling of PEPHC1, a peptide selective towards the cancer‐specific mutation of the epidermal growth factor receptor (EGFRvIII), and a number of truncated and mutated analogues. Conjugation of the peptides with [¹⁸F]FPyME was achieved within 10 min in non‐decay‐corrected radiochemical yields of 30–50%. The high yield of the conjugation reaction combined with its short synthesis time allows the labelling of several peptides from a single batch of [¹⁸F]FPyME. 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.     

Fully automated synthesis and coupling of [18F]FBEM to glutathione using the iPHASE FlexLab module

Site‐specific radiolabelling of peptides or antibodies using [¹⁸F]FBEM is often preferred over non‐site‐specific radiolabelling with [¹⁸F]SFB because it does not affect the affinity of the antibody to its target. Unfortunately, the synthesis of [¹⁸F]FBEM and its conjugation to thiol containing macromolecules requires some manual intervention, which leads to radiation exposure of the radiochemist. In this publication, we report on the complete automation of [¹⁸F]FBEM production and its subsequent conjugation to glutathione using a slightly modified iPHASE FlexLab module. [¹⁸F]FBEM was produced in 1.185 ± 0.168 GBq (15–20%; n = 10; 0.75 ± 0.106 GBq non‐decay corrected) with a specific activity of 57 ± 10 GBq/µmol. Radiochemical purity was 97 ± 1% and the synthesis time including HPLC purification and reformulation was 70 min. After evaporation to dryness, [¹⁸F]FBEM was conjugated to glutathione in PBS buffer pH 7.4 in quantitative yields. This fully automated method does not require any manual intervention and therefore reduces the radiation exposure to the operator.     

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.     

N‐2‐(4‐N‐(4‐[18F]Fluorobenzamido)phenyl)‐propyl‐2‐propanesulphonamide: synthesis and radiofluorination of a putative AMPA receptor ligand

Arylpropylsulphonamides are in the focus of research as α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolpropionic acid (AMPA) receptor ligands. A new fluorine‐18‐labelled potentiator of AMPA receptors was synthesized as a potential radiotracer for cerebral imaging with positron emission tomography. Using N‐2‐(4‐N‐(4‐nitrobenzamido)phenyl)‐propyl‐2‐propanesulphonamide ( 7 ) as labelling precursor for a Kryptofix 2.2.2^®/K₂CO₃‐activated nucleophilic radiofluorination, the putative AMPA receptor ligand N‐2‐(4‐N‐(4‐[¹⁸F]fluorobenzamido)phenyl)‐propyl‐2‐propanesulphonamide [¹⁸F] 8 was obtained in one step. Optimization of the reaction parameters time, temperature, solvent and concentration gave a radiochemical yield of 38±8% at 180°C in dimethylsulphoxide within 30‐min reaction time. After a solid‐phase extraction followed by a high‐performance liquid chromatography separation, the product could be obtained in radiochemical yields of 5±1.5%. Radiochemical purity was higher than 95% and the specific activity amounted to 77±40 GBq/µmol. First in vitro assays with rat brain slices revealed a high non‐specific binding and a uniform distribution of [¹⁸F] 8 not lending it for in vivo imaging purposes. Copyright © 2007 John Wiley & Sons, Ltd.     

Automated preparation of 2‐[18F]fluoropropionate labeled peptides using a flexible,multi‐stage synthesis platform (iPHASE Flexlab)

Radiolabelled peptides are vital tools used in positron emission tomography imaging for the diagnosis of disease, drug discovery, and biomedical research. Peptides are typically labeled through conjugation to a radiolabelled prosthetic group, which usually necessitates complex, multi‐step procedures, especially for fluorine‐18 labeled peptides. Herein, we describe the automated synthesis and formulation of 2‐[¹⁸F]fluoropropionate labeled RGD‐peptides through use of the iPHASE Flexlab as an effective dual‐stage radiochemical synthesis module. The fully automated preparation of the monomeric RGD‐peptides, [¹⁸F]FP‐GalactoRGD and [¹⁸F]FP‐c(RGDy(SO₃)K), was accomplished in under 90 minutes with n.d.c. radiochemical yields ca. 7% from fluoride. Similarly, the automated preparation of the dimeric RGD‐peptides, [¹⁸F]F‐PRGD₂ and [¹⁸F]FP‐E(RGDy(SO₃)K)₂, was accomplished in under 105 minutes with n.d.c. yields ca. 4% from fluoride.     

Rapid synthesis of maleimide functionalized fluorine‐18 labeled prosthetic group using “radio‐fluorination on the Sep‐Pak” method

Following our recently published fluorine‐18 labeling method, “Radio‐fluorination on the Sep‐Pak”, we have successfully synthesized 6‐[¹⁸F]fluoronicotinaldehyde by passing a solution (1:4 acetonitrile: t‐butanol) of its quaternary ammonium salt precursor, 6‐(N,N,N‐trimethylamino)nicotinaldehyde trifluoromethanesulfonate ( 2 ), through a fluorine‐18 containing anion exchange cartridge (PS‐HCO₃). Over 80% radiochemical conversion was observed using 10 mg of precursor within 1 minute. The [¹⁸F]fluoronicotinaldehyde ([¹⁸F] 5 ) was then conjugated with 1‐(6‐(aminooxy)hexyl)‐1H‐pyrrole‐2,5‐dione to prepare the fluorine‐18 labeled maleimide functionalized prosthetic group, 6‐[¹⁸F]fluoronicotinaldehyde O‐(6‐(2,5‐dioxo‐2,5‐dihydro‐1H‐pyrrol‐1‐yl)hexyl) oxime, 6‐[¹⁸F]FPyMHO ([¹⁸F] 6 ). The current Sep‐Pak method not only improves the overall radiochemical yield (50 ± 9%, decay‐corrected, n = 9) but also significantly reduces the synthesis time (from 60‐90 minutes to 30 minutes) when compared with literature methods for the synthesis of similar prosthetic groups.     

Radioiodine labelling of a small chemotactic peptide,utilizing two different prosthetic groups: a comparative study

The use of iodobenzoates as pre‐labelled prosthetic groups in the radioiodination of peptides is becoming increasingly popular. The utilization of an iodovinyl ester unit as an alternative conjugation agent for the preparation of a radioiodinated peptide conjugate (peptide‐[¹²³I]I‐PEA) was investigated in this study. A pre‐labelled unit, containing a tetrafluorophenyl ester group, was purified on a small C18 column and the dimethylformamide eluate was used directly in the conjugation step. Similar methodology was applied for a comparative radiosynthesis of an iodobenzoate analogue (peptide‐[¹²³I]IB), using a succinimidyl ester. The influences of various reaction parameters on conjugation yields were investigated while maintaining a fixed amount of peptide. At high activity levels (more than 200 MBq) the conjugation yield of peptide‐[¹²³I]I‐PEA was very sensitive to relatively large reaction volumes and increased amount of base. By optimizing these parameters, the formation of radiochemical impurities was minimized. Under similar conditions, peptide‐[¹²³I]I‐PEA formed much faster than peptide‐[¹²³I]IB. Sep‐Pak C18 purification afforded conjugates with radiochemical purities both in excess of 98% and free from unreacted peptide. Recovered conjugation yields of peptide‐[¹²³I]I‐PEA in 50% ethanol were in excess of 60%, while those for peptide‐[¹²³I]IB were less than 40%. Copyright © 2008 John Wiley & Sons, Ltd.     

Fully automated,high yielding production of N‐succinimidyl 4‐[18F]fluorobenzoate ([18F]SFB), and its use in microwave‐enhanced radiochemical coupling reactions

A General Electric Medical Systems (GEMS) Tracerlab FX_FN fluorine‐18 synthesis module has been reconfigured to allow rapid (45 min), fully automated production of N‐succinimidyl 4‐[¹⁸F]fluorobenzoate ([¹⁸F]SFB) using the established three‐step, one‐pot synthesis procedure. Purification is by sep‐pak only and [¹⁸F]SFB is routinely obtained in 38% non‐decay corrected yield,>1 Ci/µmol specific activity, and >95% radiochemical purity (n=20). Moreover, this report includes our preliminary research efforts into improving peptide coupling reactions with [¹⁸F]SFB using microwave‐enhanced radiochemistry. Reaction times can be reduced by>90%, when compared with traditional thermal reactions, with no significant effect on radiochemical reaction yield. Copyright © 2010 John Wiley & Sons, Ltd.     

Radiosynthesis and bioconjugation of [18F]FPy5yne,a prosthetic group for the 18F labeling of bioactive peptides

A new ¹⁸F‐based prosthetic group has been prepared for the labeling of azide‐modified peptides for use in PET imaging. 2‐[¹⁸F]fluoro‐3‐(hex‐5‐ynyloxy)pyridine ([¹⁸F]FPy5yne, [¹⁸F]‐1) was prepared via efficient nucleophilic heteroaromatic substitution of either the corresponding 2‐nitro (2) or 2‐trimethylammonium trifluoromethanesulfonate pyridine (3). Best radiochemical yield of [¹⁸F]FPy5yne from 2 was 91% by radioTLC (15 min, 110°C, DMSO). From 3, best radiochemical yield by radioTLC was 93% (15 min, 110°C, MeCN). HPLC‐purified [¹⁸F]FPy5yne was ligated to model peptide N₃–(CH₂)₄–CO–YKRI–OH by way of Cu^I‐mediated Huisgen [3+2] cycloaddition in the presence of copper‐stabilizing ligand tris(benzyltriazolylmethyl)amine (TBTA) and N,N‐diisopropylethylamine (DIEA). Bioconjugate radiochemical yields were obtained in average yields of 89%±8.6% (n=4), as judged by radioHPLC. Best non‐decay‐corrected, collected radiochemical yield of modified peptide from end‐of‐bombardment was 5.8% (18.7% decay‐corrected), with a total preparation time of 160 min from start of synthesis. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of 2‐[(2‐chloro‐2′‐[18F]fluoroethyl)amino]‐2H‐1,3,2‐oxazaphosphorinane‐2‐oxide (18F‐fluorocyclophosphamide), a potential tracer for breast tumor prognostic imaging with PET

A fluorine‐18 labeled analog of the widely used chemotherapeutic agent cyclophosphamide was synthesized as a tracer for prognostic imaging with positron emission tomography. 2‐[(2‐Chloro‐2′‐[¹⁸F]fluoroethyl)amino]‐2H‐1,3,2‐oxazaphosphorinane‐2‐oxide (¹⁸F‐fluorocyclophosphamide), was prepared by direct halogen exchange reaction from the parent cyclophosphamide. In small‐scale syntheses, radiochemical yields of up to 4.9% and specific activities of 960 Ci/mmol were achieved in a total synthesis time of 60–75 min. The [¹⁸F]‐labeled cyclophosphamide analog with radioactive purity >99% and chemical purity >96% was suitable for in vivo (microPET imaging) and ex vivo studies of a murine model of human breast tumors. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of N‐(3‐[18F]Fluoropropyl)‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)nortropane ([18F]FP‐β‐CIT)

N‐(3‐[¹⁸F]fluoropropyl)‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)nortropane ([¹⁸F]FP‐β‐CIT) was synthesized in a two‐step reaction sequence. In the first reaction, 1‐bromo‐3‐(nitrobenzene‐4‐sulfonyloxy)‐propane was fluorinated with no‐carrier‐added fluorine‐18. The resulting product, 1‐bromo‐3‐[¹⁸F]‐fluoropropane, was distilled into a cooled reaction vessel containing 2β‐carbomethoxy‐3β‐(4‐iodophenyl)‐nortropane, diisopropylethylamine and potassium iodide. After 30 min, the reaction mixture was subjected to a preparative HPLC purification. The product, [¹⁸F]FP‐β‐CIT, was isolated from the HPLC eluent with solid‐phase extraction and formulated to yield an isotonic, pyrogen‐free and sterile solution of [¹⁸F]FP‐β‐CIT. The overall decay‐corrected radiochemical yield was 25 ± 5%. Radiochemical purity was > 98% and the specific activity was 94 ± 50 GBq/µmol at the end of synthesis. Copyright © 2006 John Wiley & Sons, Ltd.     

18F‐labelling of a potent nonpeptide CCR1 antagonist: synthesis of 1‐(5‐chloro‐2‐{2‐[(2R)‐4‐(4‐[18F]fluorobenzyl)‐2‐methylpiperazin‐1‐yl]‐2‐oxoethoxy}phenyl)urea in an automated module

The synthesis of 1‐(5‐chloro‐2‐{2‐[(2R)‐4‐(4‐[¹⁸F]fluorobenzyl)‐2‐methylpiperazin‐1‐yl]‐2‐oxoethoxy}phenyl)urea ( [¹⁸F]4 ), a potent nonpeptide CCR1 antagonist, is described as a module‐assisted two‐step one‐pot procedure. The final product was obtained utilizing the reductive amination of the formed 4‐[¹⁸F]fluorobenzaldehyde ( 2 ) with a piperazine derivative 3 and sodium cyanoborohydride. After HPLC purification of the final product [¹⁸F]4 , its solid phase extraction, formulation and sterile filtration, the isolated (not decay‐corrected) radiochemical yields of [¹⁸F]4 were between 7 and 13% (n=28). The time of the entire manufacturing process did not exceed 95 min. The radiochemical purity of [¹⁸F]4 was higher than 95%, the chemical purity ?60% and the enantiomeric purity >99.5%. The specific radioactivity was in the range of 59–226 GBq/µmol at starting radioactivities of 23.6–65.0 GBq [¹⁸F]fluoride. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of N‐(piperidin‐1‐yl)‐5‐(4‐methoxyphenyl)‐1‐(2‐chlorophenyl)‐4‐[18F]fluoro‐1H‐pyrazole‐3‐carboxamide by nucleophilic [18F] fluorination: a PET radiotracer for studying CB1 cannabinoid receptors

The feasibility of nucleophilic displacement of bromide in the 4‐bromopyrazole ring with [¹⁸F]fluoride has been demonstrated by the synthesis of two radiolabeled compounds: N‐(piperidin‐1‐yl)‐5‐(4‐methoxyphenyl)‐1‐(2‐chlorophenyl)‐4‐[¹⁸F]fluoro‐1H‐pyrazole‐3‐carboxamide, ([¹⁸F] NIDA‐42033) 1b and 1‐(2‐chlorophenyl)‐4‐[¹⁸F]fluoro‐5‐(4‐methoxyphenyl)‐1H‐pyrazole‐3‐carboxylic acid, ethyl ester 4 . The radiochemical yields were in the range of 1–6%. [¹⁸F]NIDA‐42033, a potential radiotracer for the study of CB₁ cannabinoid receptors in the animal brain by positron emission tomography, has been synthesized in sufficient quantities with specific radioactivity greater than 2500 mCi/μmol and radiochemical purity >95%. Copyright © 2002 John Wiley & Sons, Ltd.