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 of tritium labeled isotopomers of L‐tyrosine

The synthesis of four selectively labeled isotopomers of L ‐tyrosine, (L ‐Tyr), using chemical and enzymatic methods is reported. Four tritium labeled isotopomers of L ‐phenylalanine (L ‐Phe) – [2‐³H]‐, [2′,6′‐³H₂]‐, [3R‐³H]‐ and [3S‐³H]‐ have been synthesized using a combination of chemical and enzymatic methods. The labeled isotopomers of L ‐Phe have been converted into [2 ‐³H]‐, [2′,6′‐³H₂]‐, [3R‐³H]‐, and [3S‐³H]‐L ‐Tyr by using the enzyme L ‐phenyl‐alanine 4′‐monooxygenase. Copyright © 2002 John Wiley & Sons, Ltd.     

Radiosynthesis and preliminary biodistribution in mice of 6‐deoxy‐6‐[131I]iodo‐L‐ascorbic acid

An ascorbate analog labeled with iodine‐131, 6‐deoxy‐ 6‐[¹³¹I]iodo‐L ‐ascorbic acid was prepared for evaluation as an in vivo tracer of L ‐ascorbic acid. The no‐carrier‐added radiosynthesis was conducted by nucleophilic bromine–iodine exchange between the brominated precursor and sodium [¹³¹I]iodide in 2‐pentanone at 130–140°C. HPLC purification using a reverse‐phase column gave 6‐deoxy‐6‐[¹³¹I]iodo‐L ‐ascorbic acid in radiochemical yield of 36–60% with high radiochemical purity and satisfactory‐specific radioactivity in a total preparation time of 90 min. Biodistribution studies in fibrosarcoma‐bearing mice showed a high uptake in the adrenal glands, accompanied by low activity of tumor accumulation, accumulation properties similar to previous results obtained with ¹⁴C‐labeled ascorbic acid and 6‐deoxy‐6‐[¹⁸F]fluoro‐L ‐ascorbic acid, in spite of high level of deiodination. Copyright © 2009 John Wiley & Sons, Ltd.     

A novel method for stereospecific fluorination at the 2′‐arabino‐position of pyrimidine nucleoside: synthesis of [18F]‐FMAU

Direct fluorination of a pyrimidine nucleoside at the 2′‐arabino‐position has been deemed to be extremely difficult, if not impossible. The conventional synthesis of 2′‐deoxy‐2′‐fluoro‐5‐methy‐1‐β‐D ‐arabinofuranosyluracil (FMAU) and its 5‐substituted analogs involves stereospecific fluorination of the 1,3,5‐tri‐O‐benzoyl‐α‐D ‐ribofuranose‐2‐sulfonate ester followed by bromination at the C₁‐postion, and then coupling with pyrimidine‐bis‐trimethylsilyl ether. Several radiolabeled nucleoside analogs, including [¹⁸F]FMAU, and other 5‐substituted analogs, were developed according to this methodology. However, routine production of these compounds using this multi‐step process is inconvenient and limits their clinical application. We developed a novel precursor and method for direct fluorination of preformed nucleoside analogs at the 2′‐arabino position, exemplified via radiosynthesis of [¹⁸F]FMAU. The 2′‐methylsulfonyl‐3′,5′‐O‐tetrahydropyranyl‐N³‐Boc‐5‐methyl‐1‐β‐D ‐ribofuranosiluracil was synthesized in multiple steps. Radiofluorination of this precursor with K¹⁸F/kryptofix produced 2′‐deoxy‐2′‐[¹⁸F]fluoro‐3′,5′‐O‐tetrahydropyranyl‐N³‐Boc‐5‐methyl‐1‐β‐D ‐arabinofuranosiluracil. Acid hydrolysis followed by high‐performance liquid chromatography purification produced the desired [¹⁸F]FMAU. The average radiochemical yield was 2.0% (decay corrected, n=6), from the end of bombardment. Radiochemical purity was >99%, and specific activity was >1800 mCi/µmol. Synthesis time was 95–100 min from the end of bombardment. This direct fluorination is a novel method for synthesis of [¹⁸F]FMAU, and the method should be suitable for production of other 5‐substituted pyrimidine analogs, including [¹⁸F]FEAU, [¹⁸F]FIAU, [¹⁸F]FFAU, [¹⁸F]FCAU, and [¹⁸F]FBAU. Copyright © 2010 John Wiley & Sons, Ltd.     

Isotopically labelled tropane alkaloids. The synthesis of (RS)‐[3′, 3′‐2H2]‐ and (RS)‐[1′‐13C, 3′, 3′‐2H2]‐ hyoscyamines for metabolism studies in plants

A synthetic route to isotopically labelled forms of the tropane alkaloid hyoscyamine, including (RS)‐[3′, 3′,‐²H₂]‐ ( 2a ) and (RS)‐[1′‐¹³C, 3′, 3′,‐²H₂]‐ ( 2b ) hyoscyamines, involving the reaction between phenylacetyl tropine and formaldehyde is described. The isotopically labelled products enable the metabolism of hyoscyamine to be studied in plants such as Datura stramonium. Copyright © 2002 John Wiley & Sons, Ltd.     

Syntheses of 5‐(2‐radiohaloethyl)‐ and 5‐(2‐radiohalovinyl)‐2′‐ deoxyuridines. Novel types of radiotracer for monitoring cancer gene therapy with PET

Syntheses of 5‐(2‐[¹⁸F]fluoroethyl)‐ ( 1 ), 5‐(2‐[⁸⁰Br]bromoethyl)‐ ( 2 ), un‐deprotected (E)‐5‐(2‐[¹⁸F]fluorovinyl)‐ ( 3 ) and (E)‐5‐(2‐[⁸⁰Br]bromovinyl)‐2′‐deoxyuridines ( 4 ) as the tracers for monitoring cancer gene therapy with positron emission tomography were described. Decay corrected radiochemical yield and synthesis time including labeling and HPLC purification from end of bombardment for 1 was 9.5% and 2 hours, respectively; yield and time for 2 was 16% and 2 hours, respectively. Chemical (approximate to radiochemical) yield and time for synthesis of 3 was 7.5% and 7 minutes, respectively. Radiochemical yield and synthesis time including labeling and HPLC purification of an analytical sample of 4 was 60% and 30 minutes, respectively. Both 2 and 4 received the side reactions during HPLC purification, i.e. ring closure and cleavage of glycosidic bond, respectively. Application of 2 and 4 needed to be confirmed by in vitro or in vivo experiments. Radiochemical yield of 1 could be optimized by employing a modified protocol for preparation of its precursor. The preparation of fluorovinyl counterparts had demonstrated the potential utility of the stannane, 3‐tolyl‐3′,5′‐di‐O‐acetyl‐(E)‐5‐(2‐stannylvinyl)‐2′‐deoxyuridine 7 . Copyright © 2003 John Wiley & Sons, Ltd.     

3H‐labelled alkyl‐nucleotides, ‐nucleosides and ‐bases for the immunoanalytical quantification of DNA damage and repair

Analysis of the formation and repair of structurally modified DNA is of particular interest in the study of carcinogenesis, cancer therapy and aging. The quantification of specific DNA lesions by sensitive immunoanalytical methods requires radiotracers with high specific activity. We describe the synthesis of ³H‐labelled adenine‐, cytosine‐, guanine‐ and thymine‐alkyl derivatives by nucleophilic N‐ and O‐alkylation using alkyl halides and diazoalkanes: 3‐alkyl‐[8‐³H]adenine (Alkyl = Me, Et, n‐Bu); O⁶‐alkyl‐deoxy[1′,2′‐³H]guanosine (Alkyl = Me, Et, i‐Pro, n‐Bu); O⁶‐ethyl‐deoxyguanosine‐5′‐triphosphate ([2‐³H‐Ethyl]; [8‐³H]); O⁶‐alkyl‐9‐hydroxyhexyl‐[8‐³H] guanine (Alkyl=Me, Et); 7‐ethyl‐[8,5′‐³H]guanosine‐3′,5′‐cyclic‐phosphate; O²‐andO⁴‐alkyl‐[methyl, 1′,2′‐³H]thymidine (Alkyl=Me, Et); the conversion of ³H‐labelled thymidine to the corresponding 5‐methylcytidine; the synthesis of three different 8‐oxo‐guanine tracers; and the generation of thymidine glycol (5,6‐dihydroxy‐5,6‐dihydro‐[methyl‐³H]thymidine) from thymidine. All radiotracers were sucessfully employed in competitive radioimmunoassays for the quantification of defined DNA alkylation products in DNA repair analyses. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and biological evaluation of a lipophilic,fluorine‐18‐labeled 5‐ethynyl‐2′‐deoxyuridine derivative

The synthesis and preliminary biological evaluation of a lipophilic, fluorine‐18‐labeled 5‐ethynyl‐2′‐deoxyuridine derivative [¹⁸F]‐ 3 is described. Initially, 5‐ethynyl‐2′‐deoxyuridine 5 was synthesized by coupling trimethylsilyl protected acetylene to 5‐iodo‐2′‐deoxyuridine 4 , followed by deprotection in alkaline conditions. Compound 5 was then reacted with 4‐(4′‐iodophenyl)phenol to give 5‐[4(4′‐hydroxyphenyl)phenyl]ethynyl‐2′‐deoxyuridine 6 . Compound 6 was reacted with BrCH₂CHF as alkylating agent to give stable or radiolabeled 3 . The crude products were purified using reversed phase‐high performance liquid chromatography to obtain compound 3 and [¹⁸F]‐ 3 in 33 and 7.4% yield (decay corrected), respectively. The synthesis time to obtain pure [¹⁸F]‐ 3 was about 60 min (starting from BrCH₂CHF). The specific radioactivity of the tracer was between 74 and 222 GBq/µmol. The log P_7.4 of [¹⁸F]‐ 3 was found to be 2.4. However, biodistribution study in normal mice showed low uptake of the tracer in the brain. The affinity of compounds 6 and 3 for varicella‐zoster virus thymidine kinase enzyme (VZV‐TK) was examined in vitro and the results revealed that the fluorinated analog 3 has a poor affinity for the enzyme in contrast to the phenol precursor 6 . Copyright © 2007 John Wiley & Sons, Ltd.     

Synthesis and preliminary characterization of radioiodinated benzofuran‐3‐yl‐(indol‐3‐yl)maleimide derivatives as potential SPECT imaging probes for the detection of glycogen synthase kinase‐3β (GSK‐3β) in the brain

We report on the synthesis and preliminary characterization of two radioiodinated benzofuran‐3‐yl‐(indol‐3‐yl)maleimides, 3‐(benzofuran‐3‐yl)‐4‐(5‐[¹²⁵I]iodo‐1‐methyl‐1H‐indol‐3‐yl)‐1H‐pyrrole‐2,5‐dione ([¹²⁵I]5), and 3‐(5‐[¹²⁵I]iodo‐1‐methyl‐1H‐indol‐3‐yl)‐4‐(6‐methoxybenzofuran‐3‐yl)‐1H‐pyrrole‐2,5‐dione ([¹²⁵I]6), as the first potential SPECT imaging probes targeting glycogen synthase kinase‐3β (GSK‐3β). In this study, we used ¹²⁵I as a surrogate of ¹²³I because of its ease of use. The radioiodinated ligands were prepared from the corresponding tributyltin precursors through an iododestannylation reaction using hydrogen peroxide as an oxidant with a radiochemical yield of 10–30%. In vitro binding experiments suggested that both compounds show high affinity for GSK‐3β at a level similar to a known GSK‐3β inhibitor. Biodistribution studies with normal mice revealed that the radioiodinated compounds display sufficient uptake into (1.8%ID/g at 10 min postinjection) and clearance from the brain (1.0%ID/g at 60 min postinjection). These preliminary results suggest that the further optimization of radioiodinated benzofuran‐3‐yl‐(indol‐3‐yl)maleimide derivatives may facilitate the development of clinically useful SPECT imaging probes for the in vivo detection of GSK‐3β.     

Fluorine‐18‐ and iodine‐125‐labelling of spiegelmers

Spiegelmers are high‐affinity l‐enantiomeric oligonucleotide ligands (aptamers) that display high resistance to enzymatic degradation compared to d‐oligonucleotides. Spiegelmers belong to the third generation of aptamers, and are currently extensively investigated as potential therapeutic agents. We have previously developed an original method to label natural oligonucleotides with radiohalogens and particularly with fluorine‐18, the most widely used positron‐emitter, t_1/2: 109.8 min. Using the same strategy, we herein report the labelling of Spiegelmers, both with fluorine‐18 for positron emission tomography imaging and iodine‐125 for high resolution autoradiography. Three 25‐mer l‐oligonucleotides have been used, differing (a) by the position of the terminal phosphorothioate monoester group (3′‐ or 5′‐end, and therefore differing by the position of the labelling on the macromolecule) and (b) by the nature of the backbone sugar moiety (2′‐OH or 2′‐H, therefore covering the RNA and DNA series, respectively). N‐(4‐[¹⁸F]fluorobenzyl)‐2‐bromoacetamide was synthesized in three radiochemical steps from 4‐cyano‐N,N,N‐trimethylanilinium trifluoromethanesulfonate and HPLC‐purified in 90 min (typical production: 2.2–2.4 GBq starting from a batch of 22–24 GBq of [¹⁸F]fluoride). N‐(4‐[¹²⁵I]iodobenzyl)‐2‐bromoacetamide was synthesized from the corresponding trimethylsilyl derivative (one pot, two radiochemical steps) and HPLC‐purified in 60 min (typical production: 24 MBq starting from 37 MBq of Na[¹²⁵I]I). Coupling of the Spiegelmers with the appropriate HPLC‐purified [radiolabelled]‐halobenzyl‐2‐bromoacetamide (MeOH/PBS (0.1 M, pH 8), 10 min, 120°C) gave the corresponding labelled conjugated Spiegelmers after RP‐HPLC purification. For fluorine‐18, the whole synthetic procedure yields up to 1.1 GBq of pure labelled Spiegelmers in 160 min with a specific radioactivity of 37–74 GBq/μmol at the end of synthesis starting from 22–24 GBq of [¹⁸F]fluoride. For iodine‐125, the whole synthetic procedure allows producing up to 7.4 MBq of pure labelled Spiegelmers in 100 min with a specific radioactivity of 11–37 GBq/μmol starting from 37 MBq of Na[¹²⁵I]I. Copyright © 2003 John Wiley & Sons, Ltd.     

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

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

Total synthesis of [13C]2‐, [13C]3‐, and [13C]5‐isotopomers of xanthohumol,the principal prenylflavonoid from hops

Xanthohumol [(E )‐6′‐methoxy‐3′‐(3‐methylbuten‐2‐yl)‐2′,4′,4″‐trihydroxychalcone], he principal prenylated flavonoid from hops, has a complex bioactivity profile, and ¹³C‐labeled isotopomers of this compound are of potential use as molecular probes and as analytical standards to study metabolism and mode of action. 1,3‐[¹³C]₂‐Xanthohumol was prepared by an adaptation of the total synthesis of Khupse and Erhardt in 7 steps and 5.7% overall yield from phloroglucinol by a route incorporating a cascade Claisen‐Cope rearrangement to install the 3′‐prenyl moiety from a 5′‐prenyl aryl ether and an aldol condensation between 1‐[¹³C]‐2′,4′‐bis(benzyloxymethyloxy)‐6′‐methoxy‐3′‐(3‐methylbuten‐2‐yl)acetophenone and 1′‐[¹³C]‐4‐(methoxymethyloxy)benzaldehyde. The ¹³C‐atom in the methyl ketone was derived from 1‐[¹³C]‐acetyl chloride while that in the aryl aldehyde was derived from [¹³C]‐iodomethane. Tri‐ and penta‐¹³C‐labeled xanthohumols were similarly prepared by applying minor modifications to the route.     

Synthesis of tritium labelled [2′,6′]‐L‐tyrosine

The synthesis of a specifically ring labelled isotopomer of L ‐tyrosine, (L ‐Tyr), using a combination of chemical and enzymatic methods is reported. The tritium labelled [2′,6′]‐L ‐Tyr has been synthesized via catalytic exchange of phenol with tritiated water in the presence of K₂PtCl₄, reverse acid catalysed removal of tritium from the o‐ and p‐positions of phenol, and subsequent condensation of the resulting [3′,5‐³H₂]‐phenol with S‐methyl‐L ‐cysteine using the enzyme β‐tyrosinase from Citrobacter freundii. Copyright © 2004 John Wiley & Sons, Ltd.     

Enzymatic synthesis of tritium‐labelled isotopomers of L‐DOPA

The synthesis of two isotopomers of L ‐DOPA labelled selectively with tritium is reported. In the intermediate step [3S‐³H]‐, and [3′,5′‐³H₂]‐L ‐tyrosine, have been obtained using a combination of chemical and enzymatic methods. The labelled isotopomers of L ‐tyrosine, L ‐Tyr, have been converted into, [3S‐³H]‐, and [5′‐³H]‐L ‐DOPA using the enzyme mushroom tyrosinase (monophenol oxidase, EC 1.14.18.1) from Neurospora crassa. Copyright © 2005 John Wiley & Sons, Ltd.     

Radiosynthesis of microtubule‐targeted theranostic methyl N‐[5‐(3’‐radiohalobenzoyl)‐1H‐benzimidazol‐2‐yl]carbamates

Microtubules are a target for a broad spectrum of drugs used as chemotherapeutics to treat hematological malignancies and solid tumors. Most of these drugs have significant dose‐limiting toxicities including peripheral neuropathies that can be debilitating and permanent. In an ongoing effort to develop safer and more effective drugs, benzimidazole‐based compounds are being developed as replacement for vincristine and similar agents. In this report, we describe radiosyntheses of novel microtubule‐targeting methyl N‐[5‐(3’‐radiohalobenzoyl)‐1H‐benzimidazol‐2‐yl]carbamates 4 that are intended as potential imaging agents and molecular radiotherapeutics. ¹²⁵I‐ and ¹³¹I‐radiolabeled derivatives were prepared either by direct radioiodination of methyl N‐(6‐benzoyl‐1H‐benzimidazol‐2‐yl)carbamate 1 or radioiododestannylation of the corresponding stannane precursor 3 . The direct radioiodination was conducted in a solution of 1 in triflic acid and produced after ~1 hour at elevated temperatures and HPLC purification on average 62% of the no‐carrier added products ¹²⁵I‐ 4 and ¹³¹I‐ 4 . Radioiododestannylation of 3’‐trimethylstannane 3 proceeded with ease at room temperature in the presence of H₂O₂ as the oxidant and produced no‐carrier‐added ¹²⁵I‐ 4 and ¹³¹I‐ 4 in high isolated yields, on average 85%. The radiohalodestannylation protocol is universal and can be applied to other radiohalides including ¹²⁴I to produce ¹²⁴I‐ 4 , a positron emission tomography agent, and ²¹¹At to produce ²¹¹At‐ 4 , an α‐particle emitting radiotherapeutic.     

Radiosynthesis of [123I]N‐(3‐iodoprop‐(2E)‐enyl)‐2α‐(imino‐methyl)‐3β‐(3′,4′‐dichlorophenyl) nortropane as a potential SPET tracer for dopamine transporter

The radiosynthesis of a novel tropane derivative [¹²³I]KUC‐25019, [[¹²³I];N‐(3‐iodoprop‐(2E)‐enyl)‐2α‐(imino‐methyl)‐3β‐(3′,4′‐dichlorophenyl)nortropane], a potential inhibitor of the dopamine transporter is reported. The synthetic routes include the preparation of standard reference, the stannyl precursor and the ¹²³I‐labeling synthesis. The no‐carrier‐added ¹²³I‐labeling has about 20% yield, the specific activity of [¹²³I]KUC‐25019 is > 107 GBq/µmol and the radiochemical purity of [¹²³I] KUC‐25019 is >95%. Copyright © 2002 John Wiley & Sons, Ltd.     

Syntheses of halogen derivatives of L‐tryptophan,L‐tyrosine and L‐phenylalanine labeled with hydrogen isotopes

Halogenated, labeled with tritium and doubly with deuterium and tritium, derivatives of L ‐tryptophan, i.e. 5′‐bromo‐[2‐³H]‐, 5′‐bromo‐[2‐²H/³H]‐, 5′‐fluoro‐[2‐³H]‐5′‐fluoro‐[2‐²H/³H]‐, 6′‐fluoro‐[2‐³H]‐, 6′‐fluoro‐[2‐²H/³H]‐L ‐tryptophan, as well as, L ‐tyrosine, i.e. 3′‐fluoro‐[2‐³H]‐, 3′‐fluoro‐[2‐²H/³H]‐, 3′‐chloro‐[2‐³H]‐, and 3′‐chloro‐[2‐²H/³H]‐L ‐tyrosine, and also L ‐phenylalanine, i.e. 2′‐fluoro‐[(3S)‐³H]‐, 2′‐fluoro‐[(3S)‐²H/³H]‐, 2′‐chloro‐[(3S)‐³H]‐, 2′‐chloro‐[(3S)‐²H/³H]‐, 4′‐chloro‐[(3S)‐³H]‐, and 4′‐chloro‐[(3S)‐²H/³H]‐L ‐phenylalanine were synthesized using enzymatic methods. Isotopomers of L ‐tryptophan were synthesized by coupling of halogenated indoles with S‐methyl‐L ‐cysteine carried out in deuteriated or tritiated incubation media. Labeled halogenated derivatives of L ‐tyrosine were obtained by the enzymatically supported exchange between halogenated L ‐tyrosine and isotopic water. Labeled halogenated isotopologues of L ‐Phe were synthesized by the enzymatic addition of ammonia to halogenated cinnamic acid. As a source of hydrogen tritiated water (HTO) and heavy water (D₂O) with addition of HTO were used.     

Synthesis and biological evaluation of 125I/123I‐labelled analogues of citalopram and escitalopram as potential radioligands for imaging of the serotonin transporter

Two novel radioligands for the serotonin transporter (SERT), [¹²⁵I]{3‐[5‐iodo‐1‐[4‐fluorophenyl)‐1,3‐dihydroisobenzofuran‐1‐yl]‐propyl}‐dimethylamine ([¹²⁵I]‐2) and S‐[¹²⁵I]{3‐[5‐iodo‐1‐(4‐fluorophenyl)‐1,3‐dihydroisobenzofuran‐1‐yl]‐propyl}‐dimethylamine ([¹²⁵I]‐(S)‐2) were synthesized in a Br/¹²⁵I exchange reaction. Binding experiments in rats yielded K_d values of 0.7 ± 0.06 and 0.52 ± 0.02 nM for [¹²⁵I]‐2 and [¹²⁵I]‐(S)‐2, respectively. One hour after intravenous injection of [¹²⁵I]‐2, 0.34% of the injected dose had accumulated in the brain. The highest hypothalamus‐to‐cerebellum ratio was reached 2 h after injection of [¹²⁵I]‐(S)‐2 and amounted to 2.4. Pre‐treatment experiments with paroxetine resulted in effective reduction of the target‐to‐cerebellum ratios. The corresponding iodine‐123 labelled compound S‐[¹²³I]{3‐[5‐Iodo‐1‐(4‐fluorophenyl)‐1,3‐dihydroisobenzofuran‐1‐yl]‐propyl}‐dimethylamine [¹²³I]‐S‐ 2 was investigated in a pig single photon emission computed tomography (SPECT) study. Between 60 and 110 min after IV injection, the midbrain‐to‐cerebellum ratio was 1.2. However, the uptake did not differ between high‐density and medium‐density regions questioning the feasibility of the radioligand in imaging cortical SERT distribution in vivo. These data suggest that the iodine‐labelled derivatives of citalopram and escitalopram are not superior to another SPECT tracer for the SERT, namely [¹²³I]ADAM. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of (E)‐2,3′,4,5′‐tetramethoxy[2‐11C]stilbene

In this paper, we describe the radiosynthesis of the compound (E)‐2,3′,4,5′‐tetramethoxy[2‐¹¹C]stilbene, a potential, universal tumour positron emission tomography imaging agent. The production of (E)‐2,3′,4,5′‐tetramethoxy[2‐¹¹C]stilbene was carried out via ¹¹C‐methylation of (E)‐2‐(hydroxy)‐3′,4,5′‐trimethoxystilbene by using [¹¹C]methyl trifluoromethanesulfonate ([¹¹C]methyl triflate). (E)‐2,3′,4,5′‐tetramethoxy[2‐¹¹C]stilbene was obtained with a radiochemical purity greater than 95% in a 20 ± 2% decay‐corrected radiochemical yield, based upon [¹¹C]carbon dioxide. Synthesis, purification and formulation were completed on an average of 30 min following the end of bombardment (EOB). The specific radioactivity obtained was 1.9 ± 0.6 GBq/µmol at EOB. Copyright © 2007 John Wiley & Sons, Ltd.     

Binding of endomorphin‐2 to μ‐opioid receptors in experimental mouse mammary adenocarcinoma

Abstract: Endomorphin‐2 (Tyr‐Pro‐Phe‐Phe‐NH₂) binds with high affinity and selectivity to the μ‐opioid receptor. In the present study, [¹²⁵I]endomorphin‐2 has been used to characterize μ‐opioid‐binding sites on transplantable mouse mammary adenocarcinoma cells. Cold saturation experiments performed with [¹²⁵I]endomorphin‐2 (1 nm ) show biphasic binding curves in Scatchard coordinates. One component represents high affinity and low capacity (K_d = 18.79 ± 1.13 nm , B_max = 635 ± 24 fmol/mg protein) and the other shows low affinity and higher capacity (K_d = 7.67 ± 0.81 μm , B_max = 157 ± 13 pmol/mg protein) binding sites. The rank order of agonists competing for the [¹²⁵I]endomorphin‐2 binding site was [d ‐1‐Nal³]morphiceptin > endomorphin‐2 ? [d ‐Phe³]morphiceptin > morphiceptin > [d ‐1‐Nal³]endomorphin‐2, indicating binding of these peptides to μ‐opioid receptors. The uptake of ¹³¹I‐labeled peptides administered intraperitoneally to tumor‐bearing mice was also investigated. The highest accumulation in the tumor was observed for [d ‐1‐Nal³]morphiceptin, which reached the value of 8.19 ± 1.14% dose/g tissue.