A facile preparation of ammonium [<Superscript>14</Superscript>C]thiocyanate

Summary An attractive and simple method has been developed for the preparation of ammonium [¹⁴C]thiocyanate from [¹⁴C]thiourea which eliminates the necessity of handling highly hazardous potassium [¹⁴C] cyanide. [¹⁴C]thiourea was isomerized to ammonium [¹⁴C]thiocyanate by heating the aqueous solution of thiourea (12%) in a sealed tube at 160 °C for 24 hours. The product formed was purified by silica-gel column chromatography. A radiochemical yield of 92.7% was obtained based on [¹⁴C]thiourea. The specific activity of the product obtained was 53.3 mCi/mmol (1.97 GBq/mmol) and the radiochemical purity was greater than 99%. This method has not been reported so far for the production of this labeled compound.     

An improved method for the preparation of [<Superscript>14</Superscript>C]thiourea of high radiochemical purity

Summary An improved method for the preparation of [¹⁴C]thiourea of high radiochemical purity is described. [¹⁴C]thiourea is prepared by the barium cyanamide route and is purified by vacuum-sublimation. The labeled product showed ammonium [¹⁴C]thiocyanate as a radiochemical impurity in the range of 2-4%. This was further purified by silica-gel column chromatography to get the product having more than 99% radiochemical purity.     

Analytical and radioanalytical quality control of purity and stability of radiopharmaceutical compound [186gRe]Re-HEDP for bone metastases pain palliation

Summary The nuclear properties of ^186gRe make it a useful agent for radionuclide therapy and imaging. The coordination compound [^186gRe]Re-HEDP has proved to be a successful bone seeking agent for palliation of metastatic bone pain. Chemical, radiochemical and radionuclidic purity of commercial radiopharmaceutical [^186gRe]Re-HEDP have been checked by means by γ- and β-spectrometries, INAA and paper radio-chromatography. The results indicate a good radionuclidic purity, with levels of contamination from the short-lived ¹⁸⁸Re well below the required specifications. After injection of the radiopharmaceutical, the radiochemical measurements conducted in vivo, on biological matrices, blood, plasma and urine, have shown that, entering the systemic circulation, ^186gRe dissociates from the bis-phosphonate complex as hydrosoluble [^186gRe]ReO₄-, and the two chemical species follow different biokinetics.     

A modified method for no carrier added radioiodination of L-tyrosine via chloramine-T as an oxidizing agent

A modified method for the preparation of L-[^131/123I] iodotyrosine as a brain imaging agent is described. The method is based on direct electrophilic radioiodination of L-tyrosine with NaI [^131/123I] using chloramine-T (CAT) and 0.001 g KI as a carrier at pH 7.0. The product was purified by reverse phase high performance liquid chromatography (HPLC). A high radiochemical yield up to 85% of L-[^131/123I] iodotyrosine has been achieved with radiochemical purity of greater than 97%. The relation between the pKa of L-tyrosine and pH of the reaction medium was calculated in order to correlate the radiochemical yield of L-[^131/123I] iodotyrosine and the state of the three ionizable groups of L-tyrosine. Also, the influence of the reaction conditions on the radiochemical yield of L-[^131/123I] iodotyrosine was investigated.     

Synthesis of <Emphasis Type="Italic">O</Emphasis>-[2-[<Superscript>18</Superscript>F]fluoro-3-(2-nitro-1<Emphasis Type="Italic">H</Emphasis>-imidazole-1-yl)propyl]tyrosine ([<Superscript>18</Superscript>F]FNT]) as a new class of tracer for imaging hypoxia

For detection of hypoxic tumor tissue, all radiotracers synthesized until now, are based on the concept that cellular uptake is being controlled by diffusion. As a new approach, we chose the concept to have the tracer hypothetically transported into the cells by well known carrier systems like the amino acid transporters. For this purpose, radiosynthesis of O-[2-[¹⁸F]fluoro-3-(2-nitro-1H-imidazole-1yl)propyl]tyrosine ([¹⁸F]FNT]) was carried out from methyl 2-(benzyloxycarbonyl)-3-(4-3-(2-nitro-1H-imidazol-1-yl)-2-(tosyloxy)propoxy) phenyl)propanoate via no-carrier-added nucleophilic aliphatic substitution. After labelling, 81 ± 0.9% of labelled intermediate i.e. methyl 2-(benzyloxycarbonyl)-3-(4-(2-[¹⁸F]fluoro-3-(2-nitro-1H-imidazole-1-yl)propoxy) phenyl)propanoate was obtained at 140 °C. At the end of radiosynthesis, [¹⁸F]FNT was obtained in an overall radiochemical yield of 40 ± 0.9% (not decay corrected) within 90 min in a radiochemical purity of >98% in a formulation ready for application in the clinical studies for PET imaging of hypoxia.     

新型除草剂丙酯草醚A环14C均标记合成和鉴定

以U-¹⁴C-对氨基苯甲酸为前体, 通过酯化、缩合、还原和取代四步反应获得了A环¹⁴C均标记的丙酯草醚, 用PHPLC对其进行纯化. 采用HPLC-MS(ESI), MS(EI)和¹H NMR验证了其结构, 通过HPLC(外标法)确定其化学纯度大于98%; HPLC-LSC和TLC-IIA两种方法分析表明, 其放射化学纯度大于98%, 其比活度为1.089±0.011 mCi/mmol. 合成的化学收率和放化收率均为53%.     

PREPARATION OF L-CYSTEINE-35S HYDROCHLORIDE BY REDUCTION OF L-CYSTINE-35S

Abstract

The method for the synthesis of L-cysteine hydrochloride labelled with ³⁵ is described. L-Cystine- ³⁵ S, obtained from baker's yeast, was reduced with tin in hydrochloric acid and radiochemical pure L-cysteine- ³⁵-hydrochloride was isolated by ion-exchange chromatography on a column.     

Synthesis of a technetium-99m-labeled thymidine analog: a potential HSV1-TK substrate for non-invasive reporter gene expression imaging

{2-[5-(2′-Fluoro-2′-deoxyuridin-5-yl)pent-4(E)-enyl] [2-(2-mercaptoethyl)aminoethyl]aminoethanethiolato(3)-N,N′,S,S′}oxo-[^99mTc]technetium(V), a potential viral thymidine kinase substrate, was synthesized by coupling 2′-fluoro-2′-deoxyuridine analog with a N2S2 radiometal chelator, followed by [Tc-99m]technetium conjugation. The chemical structure of the radioactive probe was characterized by ¹H NMR and high resolution MS using Re-188 conjugated mimics. The radiochemical purity and yield were identified as 98% and 42%, respectively.     

Optimization of the preparation conditions of radioiodoepidepride: A dopamine D<Subscript>2</Subscript>receptor antagonist radioligand

Summary [¹²⁵I]iodepidepride, (s)-(-)-[(1-ethyl-2-pyrrolidinyl)methyl]-5-[¹²⁵I]-iodo-2,3-dimethoxybenzamide is the iodine substituted analogue of isoremoxipride, both of which are very potent dopamine D₂-antagonists. Epidepride was radioiodinated using different oxidizing agents such as chloramine-T, iodogen, iodogen glass frit and hydrogen peroxide. Chloramine-T is a powerful oxidizing agent compared to both iodogen and hydrogen peroxide so that the side products, especially the chlorinated epidepride, decreases the radiochemical yield. This chlorinated epidepride is minimized in the case of iodogen and iodogen glass frit and are not observed in case of the non-chlorinated oxidizing agent hydrogen peroxide. TLC and HPLC were used to analyze the reaction components and to estimate both the radiochemical yield and purity. The reaction parameters such as reaction time, pH, epidepride and oxidizing agent concentrations and the stabilty of the final product were studied to optimize the radiochemical yield and purity. The optimized radiochemical yield was about 90% and the radiochemical purity of the final product was 99.9%.     

Synthèse du méthanesulfonate de (pyrimidyl-2)-1-(méthylène)-(dioxy-3, 4-benzyl)-4-pipérazinium (Piribedil) marqué au 14C

The synthesis of crystalline 1-(2-pyrimidyl)-4-(3, 4-methylenedioxybenzyl)-piperazin methanesulfonate (ET 495) labelled with ¹⁴C fixed on the piperazine nitrogen N(4) has been realized in five steps from barium carbonate ¹⁴C; Specific activity of the final product: 32,8 mCi/mmol (110 m?Ci/mg); radiochemical purity: around 99%. The mass spectrum of the labelled compound is in agreement with the chemical structure and the labelling position expected.     

Stability of L-[S-methyl-11C]methionine solutions

For clinical PET studies L-[S-methyl-¹¹C]methionine ([¹¹C]MET) solutions have been prepared in both high doses and specific activities (up to 48.1 GBq and 370 GBq/mmol, respectively) with high radiochemical purity (>99%). The stability of these preparations was investigated by HPLC to ensure the radiopharmaceutical efficacy during the usable shelf life. Under our routine conditions the observed radiochemical purity loss never exceeded 3.5% one hour after EOS. The decomposition rate was affected by total activity and chemical composition of the solutions.     

Partition coefficient of [3H] stobadin: Its application as an indicator of radiochemical purity

A simple and rapid method is described for the estimation of the radiochemical purity of [³H] stobadin. The proposed method uses the value of the partition coefficient /P/ as an indicator of radiochemical purity.     

Preparation of high purity labelled Rose-Bengal with radioiodine

The exchange of Rose-Bengal in the mono-sodium salt with elementary¹³¹I in an organic medium allows for the preparation of a labelled product substantially higher in radiochemical purity than that produced by other methods. Purification of the starting material before the labelling process has been done by adsorption chromatography. Under the conditions described a radiochemical yield more than 97% can be obtained within 30–60 minutes. The product was stable during sterilization and storage for 10 days and was found to be free of¹³¹I.     

Preparation of tritium-labelled oleic acid and prostaglandins E2 and F1α. A study of the process of including tritium in molecules of unsaturated fatty acids and prostaglandins

[³H]Prostaglandin E₂ and [³H]prostaglandin F_1a have been obtained with the aid of heterogeneous catalytic isotope exchange with gaseous tritium in solution. The distribution of the tritium in the labelled unsaturated fatty acids and prostaglandins has been studied.Institute of Molecular Genetics, Academy of Sciences of the USSR, Moscow. M. M. Shemyakin Institute of Bioorganic Chemistry, Khimiya Prirodnykh Soedinenii, No. 2, pp. 148–157, March–April, 1980.     

Fully Automated Macro- and Microfluidic Production of [68Ga]Ga-Citrate on mAIO® and iMiDEVTM Modules

⁶⁸Ga-radionuclide has gained importance due to its availability via ⁶⁸Ge/⁶⁸Ga generator or cyclotron production, therefore increasing the number of ⁶⁸Ga-based PET radiopharmaceuticals available in clinical practice. [⁶⁸Ga]Ga-citrate PET has been shown to be prominent for detection of inflammation/infection of the musculoskeletal, gastrointestinal, respiratory, and cardiovascular systems. Automation and comparison between conventional and microfluidic production of [⁶⁸Ga]Ga-citrate was performed using miniAllInOne^® (Trasis) and iMiDEV™ (PMB-Alcen) synthetic modules. Fully automated procedures were elaborated for cGMP production of tracer. In order to facilitate the tracer approval as a radiopharmaceutical for clinical use, a new method for radiochemical identity determination by HPLC analysis to complement standard TLC radiochemical purity measurement was developed. The results showed higher radiochemical yields when using MCX cartridge on the conventional module mAIO^®, while a PS-H+ cation exchanger was shown to be preferred for integration into the microfluidic cassette of iMiDEV™ module. In this study, the fully automated radiosynthesis of [⁶⁸Ga]Ga-citrate using different synthesizers demonstrated reliable and reproducible radiochemical yields. In order to demonstrate the applicability of [⁶⁸Ga]Ga-citrate, in vitro and in vivo studies were performed showing similar characteristics of the tracer obtained using macro- and microfluidic ways of production.     

Synthesis of <Emphasis Type="Italic">O</Emphasis>-(2-[<Superscript>18</Superscript>F]fluoroethyl)-<Emphasis Type="Italic">L</Emphasis>-tyrosine and its biological evaluation in B16 melanoma-bearing mice as PET tracer for tumor imaging

O-(2-[¹⁸F]fluoroethyl)-L-tyrosine ([¹⁸F]FET), a fluorine-18 labeled analogue of tyrosine, has been synthesized and biologically evaluated in tumor-bearing mice. The whole synthesis procedure is completed within 50 min. The radiochemical yield is about 40% (no decay corrected) and radiochemical purity more than 97% after simplified solid phase extraction. [¹⁸F]FET shows rapid, high uptake and long retention in the tumor as well as low uptake in the brain. The ratios of tumor-to-muscle (T/M) and tumor-to-blood (T/B) of [¹⁸F]FET are similar to those of [¹⁸F]FDG, but the ratios of tumor-to-brain (T/Br) are 2–3 times higher than that of [¹⁸F]FDG. Autoradiography of [¹⁸F]FET demonstrates a remarkable accumulation in melanoma with high contrast. It appears to be a probable competitive candidate for melanoma imaging with PET. Supported by the Knowledge Innovation Project of Chinese Academy of Sciences (No. KJCX1-SW-08) and the National Natural Science Foundation of China (Grant No. 30371634)     

(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.     

Module-assisted one-pot synthesis of [18F]SFB for radiolabeling proteins

The need of reliable production of N-succinimidyl 4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB), a versatile ¹⁸F-labeled prosthetic group for protein labeling, has increased dramatically due to the easy availability of proteins or their engineered derivatives for targeted molecular imaging. A module-assisted radiosynthesis of [¹⁸F]SFB was developed using a three-step, one-pot procedure and ethyl 4-(trimethylammonium)benzoate triflate (1) as the starting material. The radiochemical transformations were carried out in a general-purpose, custom-made module and streamlined by an anhydrous deprotection strategy using t-BuOK/DMSO. After HPLC-purification, [¹⁸F]SFB was synthesized in radiochemical yields of 20–30% (n > 10, not decay-corrected) and excellent radiochemical and chemical purities (>98%). The total synthesis and purification time required is ~90 min. Using the purified [¹⁸F]SFB, three ¹⁸F-labeled proteins, bovine serum albumin (BSA), chicken egg albumin (CEA) and transferrin, were synthesized in yields of 61.0–79.5%. The ¹⁸F-Annexin V for apoptosis imaging was also produced in 5% radiolabeling yield and >95% radiochemical purity.     

Production of high yield [13N] ammonia by proton irradiation from pressurized aqueous solutions

The method of direct production of large quantities of [¹³N]ammonia in the cyclotron water target for clinical cardiac studies by PET or synthetic uses was considered. Two main approaches based on the proton irradiation either of dilute aqueous ethanol solution under helium pressure or pure water pressurized by hydrogen were evaluated. Using ethanol as a target additive at the relatively low helium pressure of 400 KPa up to 22.2 GBq (600 mCi, EOB) of final product can be produced with radiochemical purity of more than 98%. Under comparable conditions the water target pressurized by hydrogen was about two times less effective for production of [¹³N]NH₃ because of the formation of considerable amounts of [¹³N]N₂. A possible mechanism of labelled nitrogen production was discussed.     

An Improved Synthesis of N-(4-[18F]Fluorobenzoyl)-Interleukin-2 for the Preclinical PET Imaging of Tumour-Infiltrating T-cells in CT26 and MC38 Colon Cancer Models

Positron emission tomography (PET) imaging of activated T-cells with N-(4-[¹⁸F]fluorobenzoyl)-interleukin-2 ([¹⁸F]FB-IL-2) may be a promising tool for patient management to aid in the assessment of clinical responses to immune therapeutics. Unfortunately, existing radiosynthetic methods are very low yielding due to complex and time-consuming chemical processes. Herein, we report an improved method for the synthesis of [¹⁸F]FB-IL-2, which reduces synthesis time and improves radiochemical yield. With this optimized approach, [¹⁸F]FB-IL-2 was prepared with a non-decay-corrected radiochemical yield of 3.8 ± 0.7% from [¹⁸F]fluoride, 3.8 times higher than previously reported methods. In vitro experiments showed that the radiotracer was stable with good radiochemical purity (>95%), confirmed its identity and showed preferential binding to activated mouse peripheral blood mononuclear cells. Dynamic PET imaging and ex vivo biodistribution studies in naïve Balb/c mice showed organ distribution and kinetics comparable to earlier published data on [¹⁸F]FB-IL-2. Significant improvements in the radiochemical manufacture of [¹⁸F]FB-IL-2 facilitates access to this promising PET imaging radiopharmaceutical, which may, in turn, provide useful insights into different tumour phenotypes and a greater understanding of the cellular nature and differential immune microenvironments that are critical to understand and develop new treatments for cancers.