Preparation and biological evaluation of 99mTc‐stannous fluoride colloid‐labelled‐leucocytes in rats 99mTc‐stannous fluoride‐labelled‐leucocytes in rats

High splenic activity is always visible in ^99mTc‐stannous fluoride (SnF₂)‐labelled‐leucocytes scans. In an attempt to reduce this activity, this study investigated the effect of pre‐injected SnF₂ colloid on the distribution of ^99mTc‐SnF₂ colloid, ^99mTc‐SnF₂‐labelled‐leucocytes, and opsonized ^99mTc‐SnF₂ colloid in rats. The radiopharmaceuticals ^99mTc‐SnF₂ colloid and ^99mTc‐SnF₂‐leucocytes were each found to exhibit identical biodistributions in separate experiments. SnF₂ colloid pre‐injection (26 μg) resulted in reduced splenic uptake of ^99mTc‐SnF₂ colloid (38%) and ^99mTc‐SnF₂‐labelled‐leucocytes (30%), but not for opsonized ^99mTc‐SnF₂ colloid. This indicates that the level of opsonization of radiocolloid is rate limiting rather than the phagocytic capacity of liver and spleen macrophages. There is a low level of ^99mTc‐SnF₂‐labelled‐leucocytes dominated by unopsonized radiocolloid in the ex vivo whole blood dose. Following administration of this dose, free radiocolloid is present in vivo that predominantly localizes in the liver and spleen. This uptake can be challenged with non‐radioactive stannous fluoride colloid pre‐injection, where splenic activity can be significantly reduced by up to 52%. Copyright © 2003 John Wiley & Sons, Ltd.     

Preparation of 68Ga‐Mg‐Ca‐phytate colloid and its evaluation as a liver imaging agent

The objective of this study was to investigate the radiosynthesis of ⁶⁸Ga‐Mg‐Ca‐phytate colloid and then characterise the formulation for radiochemical purity (RCP), radioactive particle size distribution, and biodistribution in normal rats. This radiocolloid was prepared by mixing an aqueous solution of phytic acid, ⁶⁸Ga³⁺ ions, a dispersant, Mg²⁺ and Ca²⁺ ions, and then heating the contents at 100°C for 5 minutes. After cooling the vial to 5°C, the solution was basified to pH 5 and stored in the cold. The resulting product contained 92±3% RCP ⁶⁸Ga‐colloidal particles and a low level (8±3%) of soluble ⁶⁸Ga‐Mg‐Ca‐phytate. Particle size experiments defined the radioactive particle population was 6±4% <20 nm, 90±6% 20 to 200 nm, and 4% were >200 nm in diameter. Intravenous injection of the ⁶⁸Ga‐colloid dispersion to rats resulted in 93% uptake by the liver plus spleen, 1% lungs, 1% total blood, and 6% in the carcass after 20 minutes. This optimal formulation remained stable at 5°C for 1½ hours in vitro, and it resulted in the same biodistribution as the formulation prepared at t  = 0 hours. The preclinical data so far indicate that ⁶⁸Ga‐Mg‐Ca‐colloid has excellent potential as a liver imaging agent.     

Physico‐chemical characterisation of 99mTc‐tin fluoride colloid agent used for labelling white cells

^99mTc–tin fluoride colloid is an agent used to label leucocytes, for the imaging and diagnosis of inflammatory conditions including Crohn's disease. Despite previous investigations, this radiolabelling agent is still poorly characterised. The aim of this work was to examine the process of formation and stability of ^99mTc–tin fluoride colloid using mass spectrometry, membrane filtration and atomic absorption spectrophotometric techniques. Tin‐oxide bonds in tin clusters were identified in the stannous fluoride reagent vial by mass spectrometry. From radioactive particle size distribution experiments, the facile disruption of radiocolloid particles with excess oxygen gas contrasted to the partial hydrolysis of Sn(II) during the formation process. Under the standard conditions, 10% of particles were determined as 1–3 µm, and this population coordinated 96% of the ^99mTc added. Colloid particle formation and the reduction of ^99mTc‐pertechnetate is discussed. Sodium fluoride may optimise 1–3 µm radioactive particle size, by regulating particle growth. ^99mTc–tin fluoride colloid is affected by positive or negative charge, as either Al, Mo ions or solid membranes, resulting in either coagulation and/or deflocculation of the particles. Copyright © 2006 John Wiley & Sons, Ltd.     

68Ga‐Ca‐phytate particles: A potential lung perfusion agent of synthetic origin prepared in a cold kit format

The objective of this study was to investigate the radiosynthesis of ⁶⁸Ga‐Ca‐phytate particles and then characterize the formulation for radiochemical purity, radioactive particle size distribution, and biodistribution in normal rats. This radiotracer was prepared using a commercial phytate cold kit after reconstitution with saline, ⁶⁸Ga‐chloride generator eluent, calcium chloride, and air, then heating at 100°C for 30 minutes to achieve 99% radiochemical purity of ⁶⁸Ga‐particles that were 21% 3–5 μm, 8% 5–15 μm, and 71% >15 μm in diameter. This optimal formulation was stable for 2 hours at room temperature. Intravenous administration of ⁶⁸Ga‐particles in rats resulted in an uptake of 93% in the lungs, 4% in the liver plus spleen, and 3% in the carcass after 20 minutes. Two‐thirds of the carcass activity was radioactive blood, likely to be ⁶⁸Ga‐transferrin. The positron emission tomography image was superior than the ^99mTc‐MAA image because it displayed high lung uptake against a low background. Low uptake by the liver, spleen did not interfere with the diagnostic quality, and faint activity in the submandibular (salivary) glands was due to ⁶⁸Ga‐transferrin. The preclinical data so far indicate that ⁶⁸Ga‐Ca‐phytate particles have good potential as a lung perfusion imaging agent.     

A potential lung perfusion imaging agent of synthetic origin

^99mTc‐labelled macroaggregated albumin (MAA) is the radiopharmaceutical routinely used for perfusion lung scans. However MAA formulations contain excipients of biological origin, that may potentially cause allergic hypersensitivity in patients. The aim of this study was to prepare a non‐biological lung imaging agent, with physiological uptake based on a mechanism of colloid localisation in the pulmonary vasculature. To a frozen stannous fluoride cold kit (RAH Radiopharmacy) was added ^99mTc‐pertechnetate (?2 GBq) in saline (1–4 ml), and the radioactive contents were mixed by rotation (40 rpm) in a syringe at room temperature for 30–180 min. The preparative conditions were varied to control particle growth by: the addition of metal ions, halide ions, or oxidants; different mixing times; and temperatures. The ^99mTc products were analysed for % radiolabelling efficiency (RE), radioactive particle size distribution (RPSD), qualitative and quantitative rat biodistribution studies. Results indicated that all radioactive particles were formed with >99% RE, and 1–47% were >8 µm. The optimum radiotracer formulation containing the highest proportion of the largest particles, was prepared by mixing SnF₂ and ^99mTc‐pertechnetate with a low [Na⁺] at room temperature for 50 min. Results from the quantitative organ assays gave 88±1% tracer in the lungs, and less than 10% in the liver and spleen. The images showed excellent, uniform lung uptake with minimal interference from liver and spleen to the lower regions of right and left lobes. In conclusion, the synthetic radiopharmaceutical ^99mTc–tin fluoride colloid can be prepared with a large particle size, from a commercially available cold kit in a simple and practical manner, and it has good potential for use as a perfusion imaging agent in lung scans. Copyright © 2006 John Wiley & Sons, Ltd.     

An improved assay for 68Ga‐hydroxide in 68Ga‐DOTATATE formulations intended for neuroendocrine tumour imaging

The objective of this study was to identify a more rapid assay for ⁶⁸Ga(OH)₃ impurity in ⁶⁸Ga‐DOTATATE formulations. Three methods were used to prepare ⁶⁸Ga(OH)₃ reference material (pharmacopoeial, bench titration and automated radiosynthesis), and four quality control methods for its assessment (thin layer chromatography, membrane filtration, HPLC and solid phase extraction). The optimal method of preparing ⁶⁸Ga(OH)₃ was by titrating ⁶⁸Ga³⁺ with buffered sodium hydroxide solutions to pH 5.6 ± 0.2. The precipitate was quantitatively isolated by membrane filtration (0.02 µm)/hydrochloric acid (HCl; pH 5.6) solvent, and also it remained 100% at the origin on instant thin layer chromatography with silica gel paper/HCl (pH 5.6) solvent. For ⁶⁸Ga‐DOTATATE samples, the thin layer chromatography technique was used with a single paper strip developed separately on two occasions, once in HCl (pH 5.6) and next in methanol solvent. This so‐called double‐developed (DD) method separated ⁶⁸Ga(OH)₃ impurity located at the origin, from ⁶⁸Ga‐DOTATATE plus ⁶⁸Ga³⁺ at ~R_f 0.4, and it was superior to the other methods. It assayed for the impurity similarly to the pharmacopoeial method. The advantages of the DD method were that it required inexpensive test materials and it reproducibly determined % ⁶⁸Ga(OH)₃ in ⁶⁸Ga‐DOTATATE in 12 min, 13 min earlier than the pharmacopoeial method. This time efficiency resulted in a surplus of 12% ⁶⁸Ga‐DOTATATE counts in the product vial, and this provided a contingency of radioactivity or time for the injection/imaging processes in the Nuclear Medicine Department.     

Convenient synthesis of 18F‐radiolabeled R‐(−)‐N‐n‐propyl‐2‐(3‐fluoropropanoxy‐11‐hydroxynoraporphine

Aporphines are attractive candidates for imaging D₂ receptor function because, as agonists rather than antagonists, they are selective for the receptor in the high affinity state. In contrast, D₂ antagonists do not distinguish between the high and low affinity states, and in vitro data suggests that this distinction may be important in studying diseases characterized by D₂ dysregulation, such as schizophrenia and Parkinson's disease. Accordingly, MCL‐536 (R‐(?)‐N‐n‐propyl‐2‐(3‐[¹⁸F]fluoropropanoxy‐11‐hydroxynoraporphine) was selected for labeling with ¹⁸F based on in vitro data obtained for the non‐radioactive (¹⁹F) compound. Fluorine‐18‐labeled MCL‐536 was synthesized in 70% radiochemical yield, >99% radiochemical purity, and specific activity of 167 GBq/µmol (4.5 Ci/µmol) using p‐toluenesulfonyl (tosyl) both as a novel protecting group for the phenol and a leaving group for the radiofluorination.     

Radiolabeling of a high potency cannabinoid subtype‐1 receptor ligand,N‐(4‐fluoro‐benzyl)‐4‐(3‐(piperidin‐1‐yl)‐indole‐1‐sulfonyl)benzamide (PipISB), with carbon‐11 or fluorine‐18

PipISB [N‐(4‐fluoro‐benzyl)‐4‐(3‐(piperidin‐1‐yl)‐indole‐1‐sulfonyl)benzamide, 9] was identified as a selective high potency CB₁ receptor ligand. Here we describe the labeling of 9 with positron‐emitters to provide candidate radioligands for imaging brain CB₁ receptors with positron emission tomography (PET). The radiolabeling of 9 was achieved by two methods, method A with carbon‐11 and method B with fluorine‐18. In method A, [¹¹C]9 was prepared in one step from [¹¹C]carbon monoxide, itself prepared from cyclotron‐produced [¹¹C]carbon dioxide. In method B, [¹⁸F]9 was prepared from cyclotron‐produced [¹⁸F]fluoride ion in a two‐stage, four‐step synthesis with [¹⁸F]4‐fluoro‐benzyl bromide as a labeling agent. The radiosynthesis time for method A was 44 min; decay‐corrected radiochemical yields (RCYs) from [¹¹C]carbon monoxide ranged from 3.1 to 11.6% and specific radioactivities ranged from 21 to 67 GBq/µmol. The radiosynthesis time for method B was 115 min; RCYs from [¹⁸F]fluoride ion ranged from 1.5 to 5.6% and specific radioactivities ranged from 200 to 348 GBq/µmol. With these methods, [¹¹C]9 and [¹⁸F]9 may be prepared in adequate activity and quality for future evaluation as PET radioligands. Copyright © 2008 John Wiley & Sons, Ltd.     

A kit formulation for the labelling of lipiodol with generator‐produced 188Re

A lyophilised kit formulation for the efficient labelling of lipiodol with generator‐produced ¹⁸⁸Re is described. This method involves the reaction of [¹⁸⁸Re^VIIO₄]^? (37–370 MBq) with SnCl₂ as a reducing agent, potassium oxalate as a reduction promoter, ascorbic acid as antioxidant and sodium gluconate as a weak chelate. The intermediate compound Na[¹⁸⁸Re^VO(gluc)₂] reacts with the sodium salt of a dithiobenzoate ligand to give the neutral complex [¹⁸⁸Re^III(PhCS₃)₂(PhCS₂)]. This complex is then quantitatively extracted with lipiodol to afford a stable solution. Radiochemical purity (RCP) was greater than 90% and the yield of extraction was about 88%. The role of the different kit components has been studied in detail to find the most efficient formulation (amount of reducing agent, antioxidant). The use of 0.8 mg of stannous chloride, with 40 mg of potassium oxalate and 30 mg of ascorbic acid, was found necessary. The stability of the ¹⁸⁸Re‐radiolabelled lipiodol has been investigated, in the presence of plasma. The radiolabelled lipiodol (¹⁸⁸Re‐SSS lipiodol) is stable at least 48 h (RCP=91.0±4.0%). Copyright © 2004 John Wiley & Sons, Ltd.     

Preparation and preliminary bioevaluation studies of 68Ga‐NOTA‐rituximab fragments as radioimmunoscintigraphic agents for non‐Hodgkin lymphoma

Rituximab is used for the treatment of non‐Hodgkin lymphoma (NHL). This study focuses on development of ⁶⁸Ga‐labeled rituximab fragments, (⁶⁸Ga‐NOTA‐F (ab′)‐rituximab and ⁶⁸Ga‐NOTA‐F (ab′)₂‐rituximab, as PET‐imaging agents for NHL. Rituximab was digested with immobilized pepsin and papain to yield F (ab′)₂ and Fab fragments respectively that were characterized by size exclusion HPLC (SE‐HPLC) and SDS‐PAGE. They were conjugated with p‐SCN‐Bn‐NOTA, labeled with ⁶⁸Ga and characterized by SE‐HPLC. Intact rituximab was labeled with gallium‐68 for comparison. Specificity of ⁶⁸Ga‐labeled immunoconjugates was ascertained by immunoreactivity and cell binding studies in Raji cells, while biodistribution studies were performed in normal Swiss mice. Gradient SDS‐PAGE under nonreducing condition showed molecular weights of F (ab′)₂‐rituximab and F (ab′)‐rituximab as approximately 100 and 40 Kd, respectively. Radiochemical purity (RCP) of ⁶⁸Ga‐NOTA‐F (ab′)₂‐rituximab and ⁶⁸Ga‐NOTA‐F (ab′)‐rituximab were 98.2 ± 0.5% and 98.8 ± 0.2% respectively with retention times of 17.1 ± 0.1 min and 19.3 ± 0.1 min in SE‐HPLC. ⁶⁸Ga‐labeled rituximab fragments were stable in saline and serum up to 2‐hour post preparation and exhibited specificity to CD20 antigen. Immunoreactivity of ⁶⁸Ga‐labeled immunoconjugates was greater than 80%. Clearance of the fragmented radioimmunoconjugates was predominantly through renal route. Preliminary results from this study demonstrate the potential of ⁶⁸Ga‐ NOTA‐F (ab′)₂‐rituximab and ⁶⁸Ga‐NOTA‐F (ab′)‐rituximab as PET imaging agents for NHL.     

Development of kit formulations for 99mTcN‐MPO: a cationic radiotracer for myocardial perfusion imaging

The objective of this study was to develop a kit formulation for [^99mTcN(mpo)(PNP5)]⁺ (MPO = 2‐mercaptopyridine oxide), (^99mTcN‐MPO) to support its clinical evaluations as a SPECT radiotracer. Radiolabeling studies were performed using three different formulations (two‐vial formulation and single‐vial formulations with/without SnCl₂) to explore the factors influencing radiochemical purity (RCP) of ^99mTcN‐MPO. We found that the most important factor affecting the RCP of ^99mTcN‐MPO was the purity of PNP5. ^99mTcN‐MPO was prepared >98% RCP (n = 20) using the two‐vial formulation. For single‐vial formulations with/without SnCl₂, β‐cyclodextrin (β‐CD) is particularly useful as a stabilizer for PNP5. The RCP of ^99mTcN‐MPO was 95–98% using β‐CD, but its RCP was only 90–93% with γ‐cyclodextrin (γ‐CD). It seems that PNP5 fits better into the inner cavity of β‐CD, which forms more stable inclusion complex than γ‐CD in the single‐vial formulations. The results from biodistribution and imaging studies in Sprague–Dawley rats clearly demonstrated biological equivalence of three different formulations. Single photon‐emission computed tomography data suggested that high quality images could be obtained at 0–30‐min post‐injection without significant interference from the liver radioactivity. Considering the ease for ^99mTc‐labeling and high RCP of ^99mTcN‐MPO, the non‐SnCl₂ single‐vial formulation is an attractive choice for future clinical studies.     

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.     

Technetium‐99m labeling and freeze‐dried kit formulation of levofloxacin (L‐Flox): a novel agent for detecting sites of infection

In this study, the labeling method of levofloxacin with technetium‐99m and its biological evaluation were described. ^99mTc‐L‐Flox was synthesized via direct complexation with technetium‐99m in the presence of stannous chloride dihydrate as reducing agent. The optimum amounts of the reactants are: 1–2 mg levofloxacin, 150 µg stannous chloride dihydrate and 48–1490 MBq pertechnetate. The reaction mixture was bring to pH 6 and kept at room temperature for 30 min. The labeled levofloxacin was stable for more than 8 h. The in vivo evaluation of ^99mTc‐L‐Flox in man‐induced inflammation models showed that this tracer was localized with different values. The live E. Coli model had the highest value which was 2.9%, the heat killed E. coli model had a value of 2.0%, and the turpentine oil model had a value of 1.2% at 24 post injection, while the non‐inflamed muscle had activity of 0.5%. All the gathered biological data support the usefulness of ^99mTc‐L‐Flox as infection imaging agent. The freeze‐dried form of Sn‐L‐Flox was prepared and found meet all the radiochemical and biological tests. Copyright © 2007 John Wiley & Sons, Ltd.     

Fusarinine C,a novel siderophore‐based bifunctional chelator for radiolabeling with Gallium‐68

Fusarinine C (FSC), a siderophore‐based chelator coupled with the model peptide c(RGDfK) (FSC(succ‐RGD)₃), revealed excellent targeting properties in vivo using positron emission tomography (PET). Here, we report the details of radiolabeling conditions and specific activity as well as selectivity for ⁶⁸Ga. ⁶⁸Ga labeling of FSC(succ‐RGD)₃ was optimized regarding peptide concentration, pH, temperature, reaction time, and buffer system. Specific activity (SA) of [⁶⁸Ga]FSC(succ‐RGD)₃ was compared with ⁶⁸Ga‐1,4,7‐triazacyclononane, 1‐glutaric acid‐4,7 acetic acid RGD ([⁶⁸Ga]NODAGA‐RGD). Stability was evaluated in 1000‐fold ethylenediaminetetraacetic acid (EDTA) solution (pH 7) and phosphate‐buffered saline (PBS). Metal competition tests (Fe, Cu, Zn, Al, and Ni) were carried out using [⁶⁸Ga]‐triacetylfusarinine C. High radiochemical yield was achieved within 5 min at room temperature, in particular allowing labeling with ⁶⁸Ga up to pH 8 with excellent stability in 1000‐fold EDTA solution and PBS. The 10‐fold to 20‐fold lower concentrations of FSC(succ‐RGD)₃ led to the same radiochemical yield compared with [⁶⁸Ga]NODAGA‐RGD with SA up to 1.8 TBq/µmol. Metal competition tests showed high selective binding of ⁶⁸Ga to FSC. FSC is a multivalent siderophore‐based bifunctional chelator allowing fast and highly selective labeling with ⁶⁸Ga in a wide pH range and results in stable complexes with high SA. Thus it is exceptionally well suited for the development of new ⁶⁸Ga‐tracers for in vivo molecular imaging with PET.     

Radiosynthesis of carbon‐11‐labelled GI181771, a new selective CCK‐A agonist

The novel CCK‐A agonist, (S)‐3‐(3‐{1‐[(isopropylphenylcarbamoyl)methyl]‐2,4‐dioxo‐5‐phenyl‐2,3,4,5‐tetrahydro‐1H‐benzo[b][1,4]diazepin‐3‐yl}ureido)benzoic acid, GI181771 ((S)‐ 1 ) has been isotopically labelled with carbon‐11 at its urea site using [¹¹C]phosgene in a one‐pot two‐step process, via the intermediate preparation of an [¹¹C]isocyanate derivative. Optimized conditions for the preparation of (S)‐[¹¹C]‐ 1 were the following: (1) Trapping of [¹¹C]phosgene (radiosynthesized from cyclotron‐produced [¹¹C]methane via [¹¹C]carbon tetrachloride using minor modifications of published processes) at room temperature for 1–2 min in 300 µl of acetonitrile containing 0.6 µmol of the appropriate (structurally complex) chiral‐amine giving the corresponding [¹¹C]isocyanate followed by (2) addition of an excess of 3‐aminobenzoic acid (40 µmol in 100 µl of THF) as the second amine giving the desired urea derivative (S)‐[¹¹C]‐ 1 and (3) high‐performance liquid chromatography (HPLC) purification on a semi‐preparative Waters Symmetry® C18. Starting from a typical 1.2 Ci (44.4 GBq) batch of [¹¹C]methane, 25–35 mCi (0.92–1.29 GBq, 6.8–9.6% decay‐corrected yield based on starting [¹¹C] methane, n = 5) of (S)‐[¹¹C]‐ 1 could be obtained within 35 min of radiosynthesis (HPLC purification and formulation as an i.v. injectable solution using a home‐made Sep‐pak®Plus C18 device included) with specific radioactivities ranging from 500 to 1500 mCi/µmol (18.5–55.5 GBq/µmol). The radiotracer preparation was a clear and colourless solution and its pH was between 5 and 7. As demonstrated by HPLC analysis, the radiolabelled product was found to be >99% chemically and radiochemically pure and the preparation was shown to be free of non‐radioactive precursors (starting amines) and radiochemically stable for at least 60 min. Finally, enantiomeric purity was found to be >99% according to chiral HPLC, demonstrating the absence of racemization during the process. Copyright © 2005 John Wiley & Sons, Ltd.     

Lactosaminated N‐succinyl‐chitosan as a liver‐targeted carrier of 99mTc in vivo for nuclear imaging and biodistribution

Lactosaminated N‐succinyl‐chitosan (LNSC), a water‐soluble biodegradable derivative of chitosan, was prepared, characterized, and investigated for nuclear imaging and body distribution. The labeling efficiency of LNSC was examined with ^99mTc, and the obtained complex was used as liver‐targeted delivery system in vivo for nuclear imaging, and its biodistribution within the body was studied. The labeling efficiency with ^99mTc was investigated for time of reaction, effect of substrate amount, effect of stannous chloride (SnCl₂) concentration, and effect of the pH of the reaction mixture, in order to approach the optimum condition for labeling technique. It was found that the maximum yield for labeling of 2.5‐mg ^99mTc‐LNSC was 96.9% when 50 µg of SnCl₂ was used at pH 3.5–5, at room temperature and 5‐min reaction time. An in vivo biodistribution study of radiolabeled LNSC was carried out in female Wistar rats, and the body distribution profile was recorded by gamma scintigraphy. The biodistribution of ^99mTc‐labeled LNSC (^99mTc‐LNSC) in each organ was calculated as a percentage of the injected dose per gram of tissue (%ID/g). ^99mTc‐LNSC was shown to be a highly potential approach for liver imaging. Moreover, the rapid excretion of LNSC through the kidneys suggests that water‐soluble chitosan derivatives are good carriers of radioactive elements that do not accumulate in the body. The results indicate that the easy and inexpensive extraction, and thus the ready availability, of chitosan and its derivatives makes them potentially useful for applications in scintigraphic imaging.     

Radiosynthesis of 6‐([18F]fluoroacetamido)‐1‐hexanoicanilide ([18F]FAHA) for PET imaging of histone deacetylase (HDAC)

Radiosynthesis of a novel substrate for histone deacetylase (HDAC), 6‐([¹⁸F]fluoroacetamido)‐1‐hexanoicanilide ([¹⁸F]FAHA, [¹⁸F]‐ 3 ) is reported. For precursor synthesis, compound 1 (6‐amino‐1‐hexanoicanilide) was prepared by the reaction of 6‐amino hexanoic acid with thionyl chloride in dichloroethane followed by addition of aniline. Compound 1 was reacted with bromoacetic anhydride in tetrahydrofuran (THF) in the presence of triethylamine to produce the precursor compound 6‐(bromoacetamido)‐1‐hexanoicanilide 2 . Fluorination reactions were performed using tetrabutylammonium fluoride in various solvents at 80°C to prepare the unlabeled reference compound 3 . Radiofluorinations were performed using either n‐Bu₄N¹⁸F or K¹⁸F/kryptofix, and the crude product was purified by high performance liquid chromatography (HPLC). The radiochemical yields were 9–13% decay corrected (d.c.) with an average of 11% using K¹⁸F/kryptofix, and specific activity >2 GBq/µmol at the end of synthesis. The synthesis time was 67–75 min from the end of bombardment (EOB). Copyright © 2006 John Wiley & Sons, Ltd.     

Radiosynthesis of 2‐exo‐(2′‐[18F]Fluoro‐3′‐(4‐fluorophenyl)‐pyridin‐5′‐yl)‐7‐azabicyclo[2.2.1]heptane ([18F]F2PhEP), a potent epibatidine‐based radioligand for nicotinic acetylcholine receptor PET imaging

2‐exo‐(2′‐Fluoro‐3′‐(4‐fluorophenyl)‐pyridin‐5′‐yl)‐7‐azabicyclo[2.2.1]heptane (F₂PhEP), a novel, epibatidine‐based, α4β2‐selective nicotinic acetylcholine receptor antagonist of low toxicity, as well as the corresponding N‐Boc‐protected chloro‐ and bromo derivatives as precursors for labelling with fluorine‐18 were synthesized from 7‐tert‐butoxycarbonyl‐7‐azabicyclo[2.2.1]hept‐2‐ene in 13, 19 and 8% overall yield, respectively. [¹⁸F]F₂PhEP was prepared in 8–9% overall yield (non‐decay‐corrected) using 1 mg of the bromo derivative in the following two‐step radiochemical process: (1) no‐carrier‐added nucleophilic heteroaromatic ortho‐radiofluorination with the activated K[¹⁸F]F‐Kryptofix^®₂₂₂ complex in DMSO using microwave activation at 250 W for 90 s, followed by (2) quantitative TFA‐induced removal of the N‐Boc protective group. Radiochemically pure (>95%) [¹⁸F]F₂PhEP (1.48–1.66 GBq, 74–148 GBq/µmol) was obtained after semi‐preparative HPLC (Symmetry^® C18, eluent aqueous 0.05 M NaH₂PO₄ CH₃CN: 78/22 (v:v)) in 75–80 min starting from an 18.5 GBq aliquot of a cyclotron‐produced [¹⁸F]fluoride production batch. 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.     

Radiosynthesis of the α4β2 nicotinic acetylcholine receptor ligand: 5‐((1‐[11C]‐methyl‐2‐(S)‐pyrrolidinyl)methoxy)‐2‐chloro‐3‐((E)‐2‐(2‐fluoropyridin‐4‐yl)vinyl)pyridine

5‐((1‐[¹¹C]‐methyl‐2‐(S)‐pyrrolidinyl)methoxy)‐2‐chloro‐3‐((E)‐2‐(2‐fluoropyridin‐4‐yl)‐vinyl)pyridine ([¹¹C]‐FPVC) was synthesized from [¹¹C]‐methyl iodide and the corresponding normethyl precursor. The average time of synthesis, purification, and formulation was 42 min with an average non‐decay‐corrected radiochemical yield of 19%. The average specific radioactivity was 359 GBq/µmol (9691 mCi/µmole) at end of synthesis (EOS). Copyright © 2006 John Wiley & Sons, Ltd.