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.     

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.     

Practical microscale one‐pot radiosynthesis of 18F‐labeled probes

High specific activity is often a significant requirement for radiopharmaceuticals. To achieve that with fluorine‐18 (¹⁸F)‐labeled probes, it is mandatory to start from no‐carrier–added fluoride and to reduce to a minimum the amount of precursor in order to decrease the presence of any pseudocarrier. In the present study, a feasible and efficient method for microscale one‐pot radiosynthesis of ¹⁸F‐labeled probes is described. It allows a substantial reduction in precursor, solvent, and reagents, thus reducing also possible side reaction in the case of base‐sensitive precursors. The method is based on the use of a small amount of Kryptofix 2.2.2/potassium [¹⁸F]fluoride in MeOH (K.222/K[¹⁸F]F‐MeOH) obtained using Oasis MAX and MCX cartridges. Five methods, differing in terms of MeOH evaporation and precursor addition, for the radiosynthesis of [¹⁸F]fallypride and [¹⁸F]FET in ≤50‐μL scale, were examined and evaluated. The method using the addition of DMSO to the K.222/K[¹⁸F]F‐MeOH solution prior to MeOH evaporation is proposed as a versatile procedure for feasible one‐pot 10‐ to 20‐μL scale radiosyntheses. This method was successfully applied also to the radiosynthesis of [¹⁸F]FES, [¹⁸F]FLT, and [¹⁸F]FMISO, with radiochemical yields comparable with those reported in the literature. Purification of a crude product by an analytical HPLC column was also demonstrated.     

Radiosynthesis and in vivo evaluation of a F‐18‐labeled pancreatic islet amyloid inhibitor

Formation of islet amyloid deposits contributes to the progressive loss of beta‐cells in Type 2 diabetes. Islet amyloid is composed of islet amyloid polypeptide (IAPP). [(N‐Me)G²⁴, (N‐Me)I²⁶]hIAPP(22–27) peptide was found to bind human IAPP with high‐affinity and inhibit fibrillogenesis. We labeled [(N‐Me)G²⁴, (N‐Me)I²⁶]hIAPP(22–27) with fluorine‐18 using N‐succinimidyl‐4‐[¹⁸F]fluorobenzoate. Results from biodistribution studies in healthy CF‐1 mice at 1 h p.i. indicated that ¹⁸F‐peptide was cleared efficiently (0.04±0.02%ID/g remained in blood). The primary route of clearance from the body appears to be hepatobiliary. Radioactivity accumulation in liver, intestine, and kidney was 6.7±2.9, 60.3±18.5, and 0.2±0.0%ID, respectively. Other organs accumulated negligible radioactivity. As normal mice do not develop pancreatic amyloid deposits, only background radioactivity was seen in pancreas. The radio‐HPLC analysis of mouse urine at 2 h p.i. showed that ～29.3% of injected ¹⁸F‐peptide excreted intact along with two additional metabolite peaks. Dynamic microPET/CT imaging of a CF‐1 mouse injected with ¹⁸F‐peptide indicated that radiotracer was rapidly taken up by liver and most of it moved into intestine within 10 min. The results provide a useful insight into the biological disposition of [(N‐Me)G²⁴, (N‐Me)I²⁶]hIAPP(22–27) that is being developed as a pancreatic amyloid inhibitor. Copyright © 2010 John Wiley & Sons, Ltd.     

In vitro binding profile and radiosynthesis of a novel 18F‐labeled azaspirovesamicol analog as potential ligand for imaging of the vesicular acetylcholine transporter

Radiolabeled vesamicol analogs are promising candidates as ligands for the vesicular acetylcholine transporter (VAChT) to enable in vivo imaging of early cholinergic degenerations in brain. The 4‐fluorobenzoyl‐substituted azaspirovesamicol derivative FBASV is one out of six novel vesamicol analogs and demonstrated most appropriate in vitro binding data. ¹⁸F‐radiolabeling was performed by microwave‐assisted nucleophilic aromatic substitution of the corresponding nitro precursor and two methods were developed for the purification of [¹⁸F]FBASV. Utilizing method A, the remaining nitro precursor was reduced to its corresponding amine, which was separated via semi‐preparative HPLC on a conventional RP column. In method B a phenyl column was used for the direct separation of [¹⁸F]FBASV and its nitro precursor, resulting in a change of the elution order and better separation parameters. Thus, [¹⁸F]FBASV was synthesized with a RCY of 16–18%, a specific activity >300 GBq/ µ mol, and a radiochemical purity of >99.5% suitable for future in vivo studies. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis and evaluation of an 18F‐labeled derivative of F3 for targeting surface‐expressed nucleolin in cancer and tumor endothelial cells

The surface overexpression of nucleolin provides an anchor for the specific attachment of biomolecules to cancer and angiogenic endothelial cells. The peptide F3 is a high‐affinity ligand of the nucleolin receptor (NR) that has been investigated as a carrier to deliver biologically active molecules to tumors for both therapeutic and imaging applications. A site‐specific PEGylated F3 derivative was radiolabeled with [¹⁸F]Al‐F. The binding affinity and cellular distribution of the compound was assessed in tumor (H2N) and tumor endothelial (2H‐11) cells. Specific uptake via the NR was demonstrated by the siRNA knockdown of nucleolin in both cell lines. The partition and the plasma stability of the compound were assessed at 37°C. The enzyme‐mediated site‐specific modification of F3 to give NODA‐PEG‐F3 (NP‐F3) was achieved. Radiolabeling with [¹⁸F]Al‐F gave ¹⁸F‐NP‐F3. ¹⁸F‐NP‐F3 demonstrated high affinity for cancer and tumor endothelial cells. The siRNA knockdown of nucleolin resulted in a binding affinity reduction of 50% to 60%, confirming cell surface binding via the NR. NP‐F3 was stable in serum for 2 h. ¹⁸F‐NP‐F3 is reported as the first ¹⁸F‐labeled F3 derivative. It was obtained in a site‐specific, high‐yield, and efficient manner and binds to surface NR in the low nanomolar range, suggesting it has potential as a tumor and angiogenesis tracer.     

Synthesis of 18F‐labelled biphenyls via SUZUKI cross‐coupling with 4‐[18F]fluoroiodobenzene

The SUZUKI reaction of organoboron compounds with 4‐[¹⁸F]fluoroiodobenzene has been developed as a novel radiolabelling technique in ¹⁸F chemistry. The cross‐coupling reaction of p‐tolylboronic acid with 4‐[¹⁸F]fluoroiodobenzene was used to screen different palladium complexes, bases and solvents. Optimized reaction conditions (Pd₂(dba)₃, Cs₂CO₃, acetonitrile, 60°C for 5 min) were further applied to the synthesis of various ¹⁸F‐labelled biphenyls bearing different functional groups. The reaction proceeded in excellent radiochemical yields of up to 94% within 5 min while showing good compatibility to many functional groups. Copyright © 2006 John Wiley & Sons, Ltd.     

Site‐specific addition of an 18F‐N‐methylaminooxy‐containing prosthetic group to a vinylsulfone modified peptide

Numerous strategies employing prosthetic groups for the radiosynthesis of ¹⁸F‐fluorinated peptides for positron emission tomography have been investigated in recent years. We have previously reported a novel [¹⁸F]prosthetic group bearing the N‐methylaminooxy functionality capable of reacting in a site‐selective manner with peptides functionalized with Michael‐acceptors. In a further extension of this methodology we demonstrate that O‐[2‐(2‐[¹⁸F]fluoroethoxy)ethyl]‐N‐methyl‐N‐hydroxylamine, [¹⁸F]4 , reacts chemoselectively with a vinylsulfone functionalized peptide. The conjugation yields were studied with respect to reaction time, level of radioactivity, peptide concentration and purity of the [¹⁸F]prosthetic group used in the conjugation reaction. Incubation at 70°C gave conjugation yields of around 80% with high radiochemical purity after 70 min at pH 5 in acetate buffer. Copyright © 2009 John Wiley & Sons, Ltd.     

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.     

Synthesis and evaluation of novel 18F‐labeled quinazoline derivatives with low lipophilicity for tumor PET imaging

Four novel ¹⁸F‐labeled quinazoline derivatives with low lipophilicity, [¹⁸F]4‐(2‐fluoroethoxy)‐6,7‐dimethoxyquinazoline ( [ ¹⁸ F]I ), [¹⁸F]4‐(3‐((4‐(2‐fluoroethoxy)‐7‐methoxyquinazolin‐6‐yl)oxy)propyl)morpholine ( [ ¹⁸ F]II ), [¹⁸F]4‐(2‐fluoroethoxy)‐7‐methoxy‐6‐(2‐methoxyethoxy)quinazoline ( [ ¹⁸ F]III ), and [¹⁸F]4‐(2‐fluoroethoxy)‐6,7‐bis(2‐methoxyethoxy)quinazoline ( [ ¹⁸ F]IV ), were synthesized via a 2‐step radiosynthesis procedure with an overall radiochemical yield of 10% to 38% (without decay correction) and radiochemical purities of >98%. The lipophilicity and stability of labeled compounds were tested in vitro. The log P values of the 4 radiotracers ranged from 0.52 to 1.07. We then performed ELISA to measure their affinities to EGFR‐TK; ELISA assay results indicated that each inhibitor was specifically bounded to EGFR‐TK in a dose‐dependent manner. The EGFR‐TK autophosphorylation IC₅₀ values of [ ¹⁸ F]I , [ ¹⁸ F]II , [ ¹⁸ F]III , and [ ¹⁸ F]IV were 7.732, 0.4698, 0.1174, and 0.1176 μM, respectively. All labeled compounds were evaluated via cellular uptake and blocking studies in HepG2 cell lines in vitro. Cellular uptake and blocking experiment results indicated that [ ¹⁸ F]I and [ ¹⁸ F]III had excellent cellular uptake at 120‐minute postinjection in HepG2 carcinoma cells (51.80 ± 3.42%ID/mg protein and 27.31 ± 1.94%ID/mg protein, respectively). Additionally, biodistribution experiments in S180 tumor‐bearing mice in vivo indicated that [ ¹⁸ F]I had a very fast clearance in blood and a relatively high uptake ratio of tumor to blood (4.76) and tumor to muscle (1.82) at 60‐minute postinjection. [ ¹⁸ F]III had a quick clearance in plasma, and its highest uptake ratio of tumor to muscle was 2.55 at 15‐minute postinjection. These experimental results and experiences were valuable for the further exploration of novel radiotracers of quinazoline derivatives.     

Development and radiosynthesis of the first 18F‐labeled inhibitor of monocarboxylate transporters (MCTs)

Monocarboxylate transporters 1 and 4 (MCT1 and MCT4) are involved in tumor development and progression. Their expression levels are related to clinical disease prognosis. Accordingly, both MCTs are promising drug targets for treatment of a variety of human cancers. The noninvasive imaging of these MCTs in cancers is regarded to be advantageous for assessing MCT‐mediated effects on chemotherapy and radiosensitization using specific MCT inhibitors. Herein, we describe a method for the radiosynthesis of [¹⁸F] FACH ((E)‐2‐cyano‐3‐{4‐[(3‐[¹⁸F]fluoropropyl)(propyl)amino]‐2‐methoxyphenyl}acrylic acid), as a novel radiolabeled MCT1/4 inhibitor for imaging with PET. A fluorinated analog of α‐cyano‐4‐hydroxycinnamic acid ( FACH ) was synthesized, and the inhibition of MCT1 and MCT4 was measured via an L‐[¹⁴C]lactate uptake assay. Radiolabeling was performed by a two‐step protocol comprising the radiosynthesis of the intermediate (E)/(Z)‐[¹⁸F] tert‐Bu‐FACH (tert‐butyl (E)/(Z)‐2‐cyano‐3‐{4‐[(3‐[¹⁸F]fluoropropyl)(propyl)amino]‐2‐methoxyphenyl}acrylate) followed by deprotection of the tert‐butyl group. The radiofluorination was successfully implemented using either K[¹⁸F]F‐K_2.2.2‐carbonate or [¹⁸F]TBAF. The final deprotected product [¹⁸F] FACH was only obtained when [¹⁸F] tert‐Bu‐FACH was formed by the latter procedure. After optimization of the deprotection reaction, [¹⁸F] FACH was obtained in high radiochemical yields (39.6 ± 8.3%, end of bombardment (EOB) and radiochemical purity (greater than 98%).     

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.     

One‐step radiosynthesis of 4‐nitrophenyl 2‐[18F]fluoropropionate ([18F]NFP); improved preparation of radiolabeled peptides for PET imaging

The versatile ¹⁸F‐labeled prosthetic group, 4‐nitrophenyl 2‐[¹⁸F]fluoropropionate ([¹⁸F]NFP), was synthesized in a single step in 45 min from 4‐nitrophenyl 2‐bromopropionate, with a decay corrected radiochemical yield of 26.2% ± 2.2%. Employing this improved synthesis of [¹⁸F]NFP, [¹⁸F]GalactoRGD — the current ‘gold standard’ tracer for imaging the expression of α_Vβ₃ integrin — was prepared with high specific activity in 90 min and 20% decay corrected radiochemical yield from [¹⁸F]fluoride.     

Carrier‐effect on palladium‐catalyzed,nucleophilic 18F‐fluorination of aryl triflates

A recently published palladium‐catalyzed preparation of fluoroarenes starting from caesium fluoride attracted interest as a new alternative for radiofluorination. To test this method, a suitable protocol for the synthesis of 4‐[¹⁸F]fluorotoluene and 1‐[¹⁸F]fluoronaphthalene as model systems has been developed. The possibility to perform the reaction under no‐carrier‐added condition was of special interest. It was found out, however, that the reaction requires the presence of carrier, thus limiting the method to syntheses of radiotracers with low specific activity. Copyright © 2012 John Wiley & Sons, Ltd.     

Facile synthesis of N‐succinimidyl 4‐[18F]fluorobenzoate ([18F]SFB) for protein labeling

An efficient preparation of N‐succinimidyl 4‐[¹⁸F]fluorobenzoate ([¹⁸F]SFB) based on a convenient three‐step, one‐pot procedure is described. [¹⁸F]Fluorination of the precursor ethyl 4‐(trimethylammonium triflate)benzoate gave ethyl 4‐[¹⁸F]fluorobenzoate. Saponification of the ethyl 4‐[¹⁸F]fluorobenzoate with aqueous tetrapropylammonium hydroxide yielded the corresponding 4‐[¹⁸F]fluorobenzoate salt ([¹⁸F]FBA), which was then treated with N,N,N,N′‐tetramethyl‐O‐(N‐succinimidyl)uronium hexafluorophosphate. The purified [¹⁸F]SFB was used for the labeling of Avastin^? (Bevacizumab) through [¹⁸F]fluorobenzoylation of the Avastin's α‐amino groups. The decay‐corrected radiochemical yields of [¹⁸F]SFB were as high as 44% (based on [¹⁸F]fluoride (n=10) with a synthesis time of less than 60 min. [¹⁸F]Avastin was produced in decay‐corrected radiochemical yields of up to 42% (n=5) within 30 min (based on [¹⁸F]SFB). The radiochemical purities of [¹⁸F]SFB and [¹⁸F]Avastin were greater than 95%. Copyright © 2008 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.     

A first synthesis of 18F‐radiolabeled lapatinib: a potential tracer for positron emission tomographic imaging of ErbB1/ErbB2 tyrosine kinase activity

Fluorine‐18‐labeled lapatinib has been successfully synthesized for the first time by the reaction of a dimethylformamide solution of meta‐[¹⁸F]fluorobenzylbromide with a Boc‐protected lapatinib precursor fragment. The reaction proceeded in the presence of K₂CO₃ at 110 °C for 10 min in a microwave and was followed by Boc‐group deprotection with trifluoroacetic acid. The overall radiochemical yield of the reaction starting from the radiofluorination of the iodonium salt was 8–12% (uncorrected, n = 6) in a 140‐min synthesis time.     

Synthesis and Bio‐Evaluation of New 18F‐Labeled Pyridaben Analogs with Improved Stability for Myocardial Perfusion Imaging in Mice

To improve the stability of ¹⁸F‐labeled pyridaben analogs for myocardial perfusion imaging, three new analogs of pyridaben ([¹⁸F]FPTP2, [¹⁸F]FPTP‐P2, and [¹⁸F]FPTP‐P3) were synthesized with ‘side chain’ modifications. The radiolabeled tracers and corresponding non‐radioactive compounds were obtained by substituting tosyl group with ^18/19F. The effect of structure modification on myocardial targeting and physicochemical properties of new tracers were evaluated in vitro and in vivo. The total radiosynthesis time of these tracers was approximately 70–90 min with high decay‐corrected radiochemical yields (36–65%) and good radiochemical purity (> 98%). These lipophilic tracers exhibited obvious improved stability in water. Studies of their biodistribution in normal Kunming mice demonstrated that [¹⁸F]FPTP2 exhibited very high initial heart uptake (39.70 ± 2.81 %ID/g at 2 min after injection) and low background in the liver, blood, and soft tissues. The heart‐to‐liver, heart‐to‐lung, and heart‐to‐blood ratios were 3.59, 19.34, and 67.34 at 15 min postinjection, respectively. Favorable myocardial targeting property and remarkable improvement of stability of [¹⁸F]FPTP2 suggest that the substitution of the phenyl ‘sidechain’ with other non‐phenyl rings has no effect on the myocardial targeting property of ¹⁸F‐labeled pyridaben analogs.     

Pharmacological characterization of 18F‐labeled vorozole analogs

Two ¹⁸F‐labeled analogs of vorozole ([¹⁸F]FVOZ and [¹⁸F]FVOO) have been developed as potential tools for the in vivo characterization of aromatase. The pharmacological properties of these radioligands were evaluated using in vitro binding and in vivo distribution studies in the rat and primate. Saturation binding studies using rat ovary gave K_D and B_max values of 0.21 ± 0.1 nM and 210 ± 20 fmol/mg, respectively, for [¹⁸F]FVOZ, and 7.6 ± 1 nM and 293 ± 12 fmol/mg, respectively, for [¹⁸F]FVOO. Organ distribution studies in rats showed the highest accumulation in the adrenal glands, with standardized uptake values (SUVs) of 15 to 20, followed by ovaries and liver with SUVs of approximately 5. Ex vivo and in vitro autoradiography of the rat brain showed specific binding of both [¹⁸F]FVOZ and [¹⁸F]FVOO mainly in the amygdala. Positron emission tomography (PET) studies were performed in the Rhesus monkey, and these showed displaceable binding in the amygdala and the hypothalamus preoptic area. The PET images were also analyzed using masked volume‐wise principal component analysis. These studies suggest that [¹⁸F]FVOZ might be a suitable tracer for the study of aromatase in vitro and in vivo, and could be an alternative to [¹¹C]vorozole in human PET studies. Copyright © 2012 John Wiley & Sons, Ltd.