Radiosynthesis of 10-(2-[18F]fluoroethoxy)-20(S)-camptothecin as a potential positron emission tomography tracer for the imaging of topoisomerase I in cancers

The preparation of 10-(2-[¹⁸F]fluoroethoxy)-20(S)-camptothecin, a potential positron emission tomography tracer for the imaging of topoisomerase I in cancers, is described. 10-(2-[¹⁸F]Fluoroethoxy)-20(S)-camptothecin was synthesized by the [¹⁸F]fluoroalkylation of the corresponding hydroxy precursor molecule with 2-[¹⁸F]fluoroethyl bromide ([¹⁸F]FEtBr) in dimethylsulfoxide (DMSO) at 55 °C for 20 min; this was followed by purification using high performance liquid chromatography (HPLC) with a total preparation time of 60 min. The overall radiochemical yield was approximately 5.4–12 % (uncorrected), and the radiochemical purity was above 96 %.     

A facile direct nucleophilic synthesis of O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) without HPLC purification

Due to favourable in vivo characteristics, its high specificity and the longer half-life of ¹⁸F (109.8 min) allowing for remote-site delivery, O-(2-[¹⁸F]fluoroethyl)-l-tyrosine ([¹⁸F]FET) has gained increased importance for molecular imaging of cerebral tumors. Consequently, the development of simple and efficient production strategies for [¹⁸F]FET could be an important step to further improve the cost-effective availability of [¹⁸F]FET in the clinical environment. In the present study [¹⁸F]FET was synthesized via direct nucleophilic synthesis using an earlier developed chiral precursor, the Ni^II complex of an alkylated (S)-tyrosine Schiff base, Ni-(S)-BPB-(S)-Tyr-OCH₂CH₂OTs. The purification method has been developed via solid phase extraction thereby omitting cumbersome HPLC purification. The suggested SPE purification using combination of reverse phase and strong cation exchange cartridges provided [¹⁸F]FET in high chemical, radiochemical and enantiomeric purity and 35 % radiochemical yield (decay-corrected, 45 min synthesis time). The method was successfully automated using a commercially available synthesis module, Scintomics Hotbox^one. Based on the current results, the proposed production route appears to be well suited for transfer into an automated cassette-type radiosynthesizers without using HPLC.     

Astatine-211 labelled proteins and their stability in vivo

In an ongoing effort to obtain quantitative, rapid kit type labelling of [¹²³I] radiopharmaceuticals, we have examined organomercury precursors of [¹²³I] 15-(para-iodophenyl)-pentadecanoic acid (IPPA). Chloromercuri derivatives of phenyl pentadecanoic acid (PPA) and the PPA ethyl ester were obtained by mercuration utilizing mercuric trifluoroacetate in trifluoroacetic acid followed by treatment with acetic acid and hydrochloric acid. The most simple compound, chloromercuri PPA, proved insoluble at room temperature in the common solvents useful for radioiodination and purification. The study was extended in a systematic way to chloromercuri PPA ethyl ester and the acetoxy mercuri PPA ethyl ester. As expected, these two compounds posessed successively more useful ranges of solvent compatibility. Iodination and [¹²³I] radioiodination were carried out with the three compounds of PPA. Chloromercuri PPA was dissolved with difficulty in acetic acid at 70°C and 71% radiochemical yield of [¹²³I] IPPA was obtained during the course of a 5 minute reaction utilizing chloramine T. The chloromercuri PPA ethyl ester was dissolved in ethyl acetate/acetic acid (2/1 v/v) at room temperature and 87% radiochemical yield of [¹²³I] IPPA was obtained following 10 minutes reaction. With the acetoxy mercuri PPA ethyl ester it was possible to conduct the radioiodination in ethanol again using chloramine T. A modest radiochemical yield (r. y.) (51%) of [¹²³I] IPPA ethyl ester was obtained after 60 min. It was possible to enhance the radiochemical yield in the presence of lithium acetate (84% r. y.). The isomeric purity of the [¹²³I] IPPA ethyl ester was unexpectedly high (99.9% para) when the radioiodination was conducted at room temperature.     

Synthesis of 15-(4-[<Superscript>131</Superscript>I]iodophenyl)pentadecanoic acid (<Emphasis Type="Italic">p</Emphasis>-IPPA) via tin-precursor using Chloramine-T as an oxidant

A rapid method for the preparation of the radioiodinated 15-(4-iodophenyl)pentadecanoic acid (p-IPPA) was developed. ¹³¹I-p-IPPA was obtained from the corresponding tin precursor and ¹³¹I-iodide using Chloramine-T as an oxidant in a radiochemical yield of 90 ± 1.4% with a radiochemical purity > 99% when performing the labeling at room temperature within a reaction time of 3 min. The study of dependences on temperature (0, 20 and 80 °C) and reaction time (1, 3, 5, 10 and 30 min) showed no yield increase with higher temperatures and prolonged reaction times but the formation of side products.     

Radioiodination of 4-benzyl-1-(3-iodobenzylsulfonyl)piperidine, 4-(3-iodobenzyl)-1-(benzylsulfonyl)piperazine and their derivatives via isotopic and non-isotopic exchange reactions

A mild and simple technique for preparing of 4-benzyl-1-(3-[¹²⁵I]iodobenzylsulfonyl)piperidine, 4-(3-[¹²⁵I]iodobenzyl)-1-(benzylsulfonyl)piperazine and their derivatives, as sigma-1 receptor ligands, with relatively high radiochemical yields via nucleophilic substitution reaction by means of isotopic and non-isotopic exchange reactions is described. Some factors affecting the radiochemical yield were commonly studied in presence of acidic medium at elevated temperature. Unfortunately, the radiochemical yields were weak. Some attempts were carried out in presence of polar aprotic solvents to enhance the radiochemical yield. N,N-Dimethylformamide was proved highly efficient for preparing of radioiodinated 4-benzyl-1-(3-iodobenzylsulfonyl)piperidine (4-B-[¹²⁵I]-IBSP, 70 ± 5.7 %) and 4-(3-iodobenzyl)-1-(benzylsulfonyl)piperazine (4-[¹²⁵I]-IBBSPz, 72 ± 6.0 %) at moderate temperature (100–105 °C) within 8 h. The specific activities of 4-B-[¹²⁵I]-IBSP and 4-[¹²⁵I]-IBBSPz (6,534.2 and 5,927.4 MBq/mmol) were obtained respectively.     

The synthesis of a new cardiac sympathetic nerve imaging agent N-[11C]CH3-dopamine and biodistribution study

In this study, we synthesized and characterized N-[¹¹C]methyl-dopamine ([¹¹C]MDA) for cardiac sympathetic nerve imaging. [¹¹C]MDA was synthesized by direct N-methylation of dopamine with [¹¹C]methyl iodide and purified by semi-preparation reverse high pressure liquid chromatography (HPLC). The total synthesis time was 45 min including HPLC purification. The radiochemical yields of [¹¹C]MDA was 20 ± 3 %, without decay correction. The radiochemical purity was >98 % and the specific activity was about 50 GBq/mmol. The biological properties of [¹¹C]MDA were evaluated by biodistribution study in normal mice. PET imaging was performed in healthy Chinese mini-swines. Biodistribution study showed that [¹¹C]MDA had high myocardium uptake. PET/CT imaging showed [¹¹C]MDA had clear and symmetrical myocardium uptake, which was blocked obviously by injecting imipramine hydrochloride. [¹¹C]MDA would be a promising candidate of radiotracer for cardiac sympathetic nervous system imaging.     

Synthesis and biological evaluation of 1-(4-(4-(4-[18F]fluorobenzyl)-1-piperazinyl)butyl)indolin-2-one as dopamine D4 receptor ligand

A potential dopamine D₄ receptor ligand, 1-(4-(4-(4-fluorobenzyl)-1-piperazinyl)butyl)indolin-2-one (4) was synthesized through a four-step process and its affinity and selectivity for dopamine D₂-like receptors was determined through in vitro receptor binding assay. [¹⁸F]4 was prepared using a one-pot two-step method with total radiochemical yield 21.2 % (decay-corrected). The molar radioactivity was around 135 GBq/μmol and the radiochemical purity was greater than 95.5 %. The partition coefficient (Log P) of [¹⁸F]4 was determined to be 2.10 ± 0.30 through octanol experiment. The in vivo biodistribution and the competitive distribution of [¹⁸F]4 in rat exposed that the tracer passes through blood–brain-barrier (BBB) and may specifically bind to D₄ receptor. Metabolite analysis revealed that there was no metabolism of [¹⁸F]4 in brain. Conclusively, these preliminary results demonstrated that [¹⁸F]4 shows promises as a radioligand for the in vivo study of dopamine D₄ receptor.     

Full automatic synthesis of [<Superscript>18</Superscript>F]THK-5351 for tau protein PET imaging in Alzheimer’s disease patients: 1 year experience

[¹⁸F]THK-5351, a new candidate for tau protein imaging, is based on an aryl quinoline structure. We report the full automatic synthesis using disposable cassettes under pH controlled [¹⁸F]fluorination. After the trapping of 88.5 ± 21.9 GBq of [¹⁸F]fluoride, it was eluted with potassium methansulfonate (KOMs) (pH 7.8)/K₂₂₂. After drying, 3 mg of the precursor was added to 1 mL DMSO and subjected to [¹⁸F]fluorination at 110 °C for 10 min. After hydrolysis, the final product was purified by HPLC. The overall radiochemical yield was 31.9 ± 11.1% (n = 22), satisfying all quality control criteria. It was stable for up to 6 h with high radiochemical purity as 99.8 ± 0.5%.     

Automated synthesis of [18F]FMISO on IBA Synthera®

In cancer cells hypoxia can cause resistance to both radio- and chemo-therapy. Being able to quantify, the degree of hypoxia in the cells is a useful tool in therapy planning. The positron emitting 1-[¹⁸F]fluoro-3-(2-nitro-1H-imidazol-1-yl)propan-2-ol ([¹⁸F]FMISO) is the most extensively used tracer for imaging hypoxia. Automated synthesis of [¹⁸F]FMISO was set up on IBA Synthera^®. The precursor 1-(2′-nitro-1′-imidazolyl)-2-O-tetrahydropyranyl-3-O-p-toluenesulfonyl propanediol (NITTP) was heated at 100 °C for 10 min with [K/K 2.2.2.]⁺[¹⁸F]^? and thereafter hydrolyzed with 0.1 M hydrochloric acid at 90 °C for 2 min. Purification was performed on solid-phase extraction (SPE) cartridges. [¹⁸F]FMISO was obtained in 50 ± 3 % (n = 6) radiochemical yield (decay-corrected) in 35 min synthesis time with radiochemical purity of ≥98 %. The use of disposable Integrated Fluid Processors (IFP?:s) and cartridge purification simplifies the handling and shortens the synthesis time. This is a no frills setup based on all commercially available materials and the synthesis is performed with minor changes from the FDG time-list.     

Reactions of Ru(Cp) complexes with P(o-tolyl)3

Reaction of [Ru(Cp^∗)(CH₃CN)₃](PF₆) with P(o-tolyl)₃ affords [Ru(Cp^∗){(η⁶-o-tolyl)P(o-tolyl)₂}](PF₆) (4) in which the P-atom is not coordinated to the metal. The solid-state structure of 4 has been determined. A related reaction with P(p-tolyl)₃ reveals a small quantity [Ru(Cp^∗){(η⁶-p-tolyl)P(o-tolyl)₂}](PF₆), in solution, but mostly the expected bis-phosphine complex. Reaction of the Ru(IV) dication, [Ru(Cp^∗)(η³-PhCHCHCH₂)(DMF)₂](PF₆)₂, with P(o-tolyl)₃ gives a mixture of the phosphonium salt, C₆H₅CHCHCH₂P(o-tolyl)₃ (9) and the dication [Ru(Cp^∗) (η⁶-C₆H₅CHCHCH₂P(o-tolyl)₃)](PF₆)₂ (10). Salt 9 forms via attack of the P-atom on the allyl ligand. The latter product results from complexation of 9 via the phenyl group of the former allyl ligand. It would seem that the sterically demanding P(o-tolyl)₃ ligand is not readily compatible with the Ru(Cp^∗) fragment, in either the +2 or +4 oxidation state. Detailed NMR studies are reported.     

N-[11C]methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB): synthesis, quality control and biodistribution

N-[¹¹C]methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine ([¹¹C]MBDB) 3 was prepared by methylation of the demethyl precursor BDB with [¹¹C]CHI. The radiosynthesis was optimized with regard to temperature, reaction time and amount of precursor, best results (i.e., 84% radiochemical yield, based on [¹¹C]CH₃I activity) were obtained using 3 mg BDB at a reaction temperature of 130 °C in 8 minutes. With respect to a facilitated workup routine, productions were performed with 0.6 mg BDB at 110 °C for 10 minutes, yielding more than 50% of 3. The radiochemical purity of the final tracer solution was >98%, the specific activity was determined to be 300 GBq/mol (8000 Ci/mmol). Biodistribution, studies in rats showed two major metabolic pathways as indicated by an increasing liver uptake (9.1% ID/organ at 5 minutes to 21% ID/organ at 30 minutes) and a high urine activity (up to 16% ID/g). In brain tracer uptake was more than 1%, with a brain to blood ratio of almost 12 resulting from a very rapid blood clearance of 3.     

Preparation, nano purification, quality control and labeling optimization of [64Cu]-5,10,15,20-tetrakis (penta fluoro phenyl) porphyrin complex as a possible imaging agent

Cu-64 was produced via the ⁶⁸Zn (p,αn)⁶⁴Cu nuclear reaction (≈200 mCi, >95 % chemical yield at 180 μA for 1.1 h irradiation, (radionuclidic purity >96 %, copper-67 as impurity) followed by purification with amino functionalized nano magnetic oxide, Fe₃O₄ aiming to remove trace amount of heavy metal ions from aqueous media due to achieve ultra pure [⁶⁴Cu] CuCl₂ for labeling step. [⁶⁴Cu] labeled 5,10,15,20-tetrakis(penta fluoro phenyl) porphyrin ([⁶⁴Cu]-TFPP) was prepared using freshly prepared [⁶⁴Cu] CuCl₂ (Cu-64; T _1/2 = 12.7 h) and 5,10,15,20-tetrakis(penta fluoro phenyl)porphyrin (H₂TFPP) for 60 min at 100 °C under reflux condition (radiochemical purity: >97 % ITLC, >98 % HPLC, specific activity: 14–16 GBq/mmol). Stability of the complex was checked in final formulation and human serum for 24 h. The partition coefficient was calculated for the compound (log P = 0.73). The biodistribution of the labeled compound in vital organs of wild-type rats was studied using scarification studies and PET imaging up in 2 and 4 h after injection. A detailed comparative pharmacokinetic study performed for ⁶⁴Cu cation and [⁶⁴Cu]-TFPP. The complex is mostly washed out from the circulation through kidneys and liver and can be an interesting tumor imaging/targeting agent due to high specific uptake and rapid excretion through the urinary tract.     

N-[11C]methyl-3,4-methylenedioxyamphetamine (Ecstasy) and 2-methyl-N-[11C]methyl-4,5-methylenedioxyamphetamine: Synthesis and biodistribution studies

In order to evaluate the neurobiological mechanism causing the psychogenic effects of methylenedioxy-derivatives of amphetamine, the carbon-11 labeled analogues of 3,4-methylenedioxymethamphetamine (MDMA),2 and 2,N-dimethyl-4,5-methylenedioxyamphetamine (MADAM-6)4 were prepared for application in in-vivo PET studies by methylation of 3,4-methylenedioxyamphetamine (MDA)1 and 2-methyl-4,5-methylenedioxyamphetamine3 with [¹¹C]CH₃I. The radiochemical yield was determined in dependence on time, temperature and amount of precursor. The best conditions for a fast labeling reaction with carbon-11 on a preparative scale were found to be a reaction time of 10 min using 1 mg of the corresponding dimethyl-precursors1 or3, thus obtaining radiochemical yields of 60% (based on produced [¹¹C]CH₃I). Biodistribution studies were performed in rats, a high brain to blood ratio of 7.5 was observed for [¹¹C]MDMA in contrast to a ratio of 3.7 for [¹¹C]MADAM-6.     

In vitro assessment of cytotoxicity, anti-inflammatory, antifungal properties and crystal structures of metallacyclic palladium(II) complexes

Metallacyclic palladium(II) complexes [Pd(L)(R₃P)Cl], L = TIQDTC (1,2,3,4-tetrahydroisoquinolinedithiocarbamate), 4MpipDTC (4-methylpipradinedithiocarbamate), MPizDTC (N-methylpiperazinedithiocarbamate), R₃P = Ph₃P, (o-tolyl)₃P, Ph₂ClP, were synthesized in a 1:1 molar metal-ligand ratio. These complexes were characterized by elemental analyses, FT-IR, multinuclear (¹H, ¹³C and ³¹P) NMR. The X-ray crystal structures of [Pd(TIQDTC)(Ph₃P)Cl] and [Pd(TIQDTC)((o-tolyl)₃P)Cl] show a slightly distorted square planar environment around the Pd(II) ion with S-Pd-S and P-Pd-Cl average bond angles of 74.51 and 92.41, respectively. These complexes were screened for cytotoxic, antifungal, anti-inflammatory and antibacterial activity. Some complexes exhibit a significant activity against fungi.     

(S)-2-((S)-2-(4-(3-[18F]fluoropropyl)benzamido)-3-phenylpropanamido)pentanedioic acid labeled with 18F

As degradation product of Antineoplaston A10 in vivo, phenylacetyl glutamine showed antitumor activities. According to literatures, we designed and radiosynthesized a phenylacetyl glutamine derivative, which was achieved under a mild reaction condition. Evaluations in vitro and in vivo were performed on tumor bearing mice. Excitingly, the radiochemical purity of (S)-2-((S)-2-(4-(3-fluoropropyl)benzamido)-3-phenylpropanamido)pentanedioic acid ([¹⁸F]FBPPA) was 98%, and besides the best radiochemical yield was up to 46%. T/Bl (Tumor/Blood) and T/M (Tumor/Muscle) ratios of [¹⁸F]FBPPA at 60 min post injection were 2.33 and 3.51. Meanwhile, it showed satisfied stability in vitro and in vivo, compared with 2-[¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG). Although [¹⁸F]FBPPA deserved further studies to make optimizations on its structure, the results revealed it might become a potential PET imaging agent for detecting tumors.     

A novel synthesis of (3,6-bis(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-9-(4-vinylbenzyl)-9H-carbazole), alternating polymer formation, characterization, and capacitance measurements

In this work, (3,6-bis(2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)-9-(4-vinylbenzyl)-9H-carbazole) (EDOTVBCz) comonomer was chemically synthesized and characterized by Fourier transform infrared (FTIR), proton nuclear magnetic resonance, and carbon nuclear magnetic resonance spectroscopy. EDOTVBCz was electrocoated on glassy carbon electrode (GCE) in various initial molar concentrations ([EDOTVBCz]₀?=?1.0, 1.5, 2.0, and 3.0) in 0.1 M lithium perchlorate (LiClO₄)/acetonitrile (CH₃CN). P(EDOTVBCz)/GCE was characterized by cyclic voltammetry, FTIR reflectance-attenuated total reflection spectroscopy, scanning electron microscopy–energy dispersive X-ray analysis, atomic force microscopy, and electrochemical impedance spectroscopy (EIS). EIS was used to determine the capacitive behaviors of modified GCE via Nyquist, Bode magnitude, Bode phase, and admittance plots. The highest low-frequency capacitance value was obtained as C _LF?=?～2.35 mF cm^?2 for [EDOTVBCz]₀?=?3.0 mM. Double-layer capacitance of the polymer/electrolyte system was calculated as C _dl?=?～2.78 mF cm^?2 for [EDOTVBCz]₀?=?1.0 and 3.0 mM. The maximum phase angle was obtained as θ?=?～76.7^o for [EDOTVBCz]₀?=?1.0, 1.5, 2.0, and 3.0 mM at the frequency of 20.6 Hz. AC impedance spectra of P(EDOTVBCz)/LiClO₄/CH₃CN was obtained by performing electrical equivalent circuit model of R(Q(R(CR))) with linear Kramers–Kronig test.

Copper(II) complexes of entwined 2,9-di(o-substituted phenyl)-1,10-phenanthroline type ligands and intramolecular quenching in copper(I) complexes

Cu¹¹ complexes of 1,10-phenanthroline, disubstituted at the 2 and 9 positions or monosubstituted at the 2 position by phenyl moieties possessingortho substituents, were prepared and investigated by spectroscopic and electrochemical methods. The electronic spectral d-d band position varies from 14 500 to 13 200 cm⁻¹. E.s.r. g_‖ values are between 2.256 to 2.283 and A_‖ between 164 to 117×10⁻⁴ cm⁻¹. Thebis[2,9-di(o-substituted phenyl)-1,10-phenanthroline]Cu¹¹ complexes undergo reversible one-electron electrochemical reduction (Cu¹¹/Cu¹) in the +0.536 to +0.825 V potential range versus s.c.e., whereas thebis[2-mono(o-substituted phenyl)-1,10-phenanthroline]Cu¹¹ complexes undergo reduction in the +0.360 to +0.405 V range; the redox couple is found to be quasireversible. Emission studies on copper(I) complexes show that onlybis[2,9-di(o-tolyl)-1,10-phen]Copper(I) complex exhibits emission properties. Emission behaviour of other structurally similar compounds is explored. TMC 2555     

Radiosynthesis and preliminary biological evaluation of the 2-[<Superscript>18</Superscript>F]fluoropropionic acid enantiomers for tumor PET imaging

The aim of this study was to synthesize the optically pure [¹⁸F]FPA, and to investigate the diagnostic value of different isomers. Semi-automated radiosynthesis of R-[¹⁸F]FPA or S-[¹⁸F]FPA was respectively from the chiral precursor (S)- or (R)-ethyl 2-(((trifluoromethyl)sulfonyl)oxy)propanoate via a two-step reaction and performed on the commercial FDG synthesizer. The improved radiochemical yields of R-[¹⁸F]FPA and S-[¹⁸F]FPA were 30–40% (decay-uncorrected, n = 10) in 35 min. There was no significant difference on the biodistribution of two enantiomers in normal mice (P > 0.05), but positron emission tomography imaging demonstrated that R-[¹⁸F]FPA was more suitable for PC3 tumor imaging than S-[¹⁸F]FPA and [¹⁸F]FDG.     

Complexation with bis(diphenylphosphino)methane of reaction products between arylcopper(I) compounds and carbon disulfide

The insertion products [ArCS₂Cudppm]₂ and [(o-tolylCS₂Cu)₂dppm]₂ (dppm  bis(diphenylphosphino)methane) were isolated after addition of dppm to CS₂ solutions of arylcopper(I) (Ar  phenyl, o-, m- and p-tolyl). Another series of complexes, tentatively assigned the formula [Cu₆(dppm)₂Ar₄C₄S₉], was also isolated. All the complexes were non electrolytes and were characterized by IR and ¹H and ³¹P NMR spectra. In addition to the [ArCS₂Cudppm]₂ complexes also the related product [(Cudppm)₄(CS₃)₂] was obtained.     

A novel strategy for the preparation of the injectable PET/CT radiopharmaceutical (-)-[11C]-(1R,2S)-meta-hydroxyephedrine ((-)-[11C]HED

Positron emission tomography (PET) had been applied in clinical early diagnosis of various tumors and other diseases. The methylated synthetic conditions of (-)-[¹¹C]-(1R,2S)-meta-hydroxyephedrine ((-)-[¹¹C]HED), considered as one of the most important radiopharmaceuticals for PET, were optimized through single factor and orthogonal design methods. Here, we reported an improved purification protocol. The radiochemical yields of the final product were over 45% (decay-corrected and based on [¹¹C]methyl iodide) (n?=?50). The radiochemical purities and chemical purities were over 99% (n?=?50) and 97% (n?=?50), respectively. The automatic radiosynthesis procedure of (-)-[¹¹C]HED with relatively high radiochemical yield was convenient and reliable.