Nucleophilic radioiodination of 6-bromocholesterol via non-isotopic exchange reaction in molten state

A synthetic method for preparing radioiodinated 6-[125 I]iodocholesterol[CL-6-125 I] for adrenal evaluation is described. The radioiodine atom wasincorporated onto the cholesterol molecule via non-isotopic exchange between6-bromocholesterol [CL-6-Br] and radioiodine as iodide ion [ 125 I –]in a molten state. The different parameters affecting the yield of exchange were investigated using 125 I (T 1/2 .60 d) to centralize the different physical and chemical reaction conditions and purification of the final product as pure as 6-[125 I]iodocholesterol. The method was suitable to either 131 I (T 1/2 .8 d) nucleophilic radioiodination which facilitates the scanning of the adrenal for a few days after administration or the use of 124 I (T 1/2 .4.16 d) nucleophilic radioiodination for PET evaluation of the adrenal. TLC as well as HPLC chromatographic analysis is used to determine the efficiency of the exchange reactions under different chemical reaction conditions and to monitor the stability of the final product as pure as CL-6-125 I with radiochemical purity of .99%. This no-carrier-added method improved the speed of the reaction and affords high radiochemical yield of 90 % and suitable specific activity due to the use of CL-6-Br rather than CL-6-I as substrate. Kinetic studies revealed second order iodine-bromine exchange reaction. The activation energy for the exchange reaction in ammonium acetate (m.p. 114 °C) was calculated to be 4.576 kcal/mole.     

Synthesis of radioiodinated 4-[*I]iodoantipyrine via isotopic exchange

Radioiodinated 4-[*I]iodoantipyrine labeled with radioiodine (i.e., ¹²³I or ¹²⁵I or ¹³¹I) has been used for modeling radiation damage on cell nuclei of tumor cells where the characteristic high linear energy transfer (high-LET) of the Auger electron could be demonstrated. Also, the compound is currently used for the measurement of regional cerebral blood flow (rCBF) in autoradiography. 4-[¹³¹I]iodoantipyrine was synthesized by two methods via a nucleophilic isotopic exchange reaction between ¹³¹I as iodide ion [¹³¹I^–] and inactive 4-[¹²⁷I]iodoantipyrine: either in absolute ethyl alcohol catalyzed by ammonium acetate or in dry state molten ammonium acetate (m.p. 114 °C) as an isotopic exchange medium without carrier addition. The first one is called wet method: where a solution of 4-iodoantipyrine and ammonium acetate in absolute ethyl alcohol and lyophilized Na¹³¹I was heated briefly up to boiling (80 to 90 °C) for 30 minutes under reflux. The second one is called dry state-molten method: where the alcoholic solution containing 4-iodoantipyrine and ammonium acetate and the lyophilized Na¹³¹I were heated briefly in a nitrogen stream to dryness at 120 to 125 °C for 5 minutes or melted by gradual heating at 150 to 160 °C for 5 minutes. A radiochemical yield ranged between 90%–95% in each method has been obtained for 4-[¹³¹I]iodoantipyrine. In both methods, the reaction proceeds properly without carrier addition by an addition – elimination mechanism. The physico-chemical parameters affecting the radiochemical yield of the isotopic exchange reaction [i.e., reaction time, temperature, exchange medium, concentration of the reactants, carrier (KI) addition and pH] were investigated. Chromatographic analysis i.e., TLC and HPLC were used to determine the radiochemical yield as well as the purity of the final product, which was as pure as 99.9%.     

Radioiodination of N-[3-(4-morphilino)propyl]-N-methyl-2-hydroxy-5-iodo-3-methyl-benzylamine (ERC9) via isotopic exchange reaction

Summary A simple method for labeling ERC9 with radioactive iodine has been carried out via nucleophilic substitution radioiodination. The factors affecting the radiochemical yield of the labeling of ERC9, such as pH of the medium, substrate concentration and temperature were investigated. Chromatographic analysis technique was used to determine the radiochemical yield and purity. Kinetics and thermodynamic parameters indicated a second order reaction. Activation energy for the isotopic exchange reaction between ERC9 and ¹²⁵I^- was calculated to be 24.4 kJ/mol.     

Dry state preparation of radioiodine labeled meta-iodobenzylguanidine

Radioiodination of meta-iodobenzylguanidine (MIBG) by the isotopic exchange technique in the dry state has been performed. Benzoic acid, pivalic acid and acetamide have been used as molten protic media to promote isotopic exchange reactions. Ammonium sulphate, diammonium hydrogen ortho-phosphate and ammonium chloride were used as catalysts which provide acidic media to facilitate exchange reactions. Maximum radiochemical yields of 97.1±1.3% and 84.3±1.6% [¹³¹I] MIBG were obtained when ammonium sulphate and benzoic acid were used. High radiochemical yields of 88.3±1.1% and 74.4±1.5% [¹³¹I] MIBG were also obtained in case of diammonium hydrogen orthophosphate and pivalic acid which suggests their successful use as reaction media in the radioiodination of MIBG. The activation energy for the exchange reaction in ammonium sulphate was calculated to be 10.8 kcal/mole.     

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.     

Fast Efficient Method for Radiolabeling of Pindolol with Iodine-125 Using Iodogen Coated Glass Frit

Although ¹²⁵I-hydroxypindolol (¹²⁵I-HYP) has been an excellent probe of adenoceptor function in certain tissues, but ¹²⁵I-pindolol (¹²⁵I-PIN) was found more specific for -adrenoceptor labeling. This study describes a fast and efficient method for radiolabeling of pindolol with iodine-125, where both chloramine-T and iodogen were used as oxidizing agents. The use of iodogen coated glass frit has a great advantage in increasing the radiochemical yield of ¹²⁵I-pindolol and this was attributed to the increase of the interphaces boundary between the solid and liquid. This technique reduces the quantity of iodogen required to produce high radiochemical yield by its half. The radiochemical yield was determined by TLC system using chloroform: acetic acid: water (15:4:1) as developing solvent and by HPLC using reversed phase RP-18 column and acetonitrile: 0.1M ammonium bicarbonate pH 7.5 (1:1) as a mobile phase at flow rate (1ml/min). The radiochemical yield was found to be 48.6 and 62.9% respectively.     

A Highly Efficient Copper‐Mediated Radioiodination Approach Using Aryl Boronic Acids

A convenient and quantitative radioiodination method by copper‐mediated cross‐coupling of aryl boronic acids was developed. The mild labeling conditions, ready availability of the boronic acid substrate, simple operation, broad functional group tolerance and excellent radiochemical yield (RCY) make this a practical strategy for radioiodine labeling without further purification.     

Radioiodination, purification and bioevaluation of Piroxicam in comparison with Meloxicam for imaging of inflammation

The present study is performed to compare the electrophilic substitution radioiodination reaction of two non-steroidal anti-inflammatory drugs namely, Piroxicam (Pirox) and Meloxicam (Melox) with ¹²⁵I where both chloramine-T (CAT) and iodogen were used as oxidizing agents. The factors affecting the percent of radiochemical yields such as drug concentration, pH of the reaction mixtures, different oxidizing agents, reaction time, temperature and different organic media were studied to optimize the conditions for labeling of Pirox and Melox and to obtain high radiochemical yields. The maximum radiochemical yield of ¹²⁵I-Piroxicam (¹²⁵I-Pirox) was 94% using 3.7 MBq of Na¹²⁵I, 0.4 mM of Pirox as substrate, 3.6 mM of chloramine-T (CAT) as oxidizing agent in acetone at neutral pH = 7 and at 60 °C within 20 min where the maximum radiochemical yield of ¹²⁵I-Melox was 92% using 0.7 mM of Melox as substrate, 0.62 mM of iodogen as oxidizing agent in acetone at neutral pH = 7 and at 25 °C within 30 min. The radiochemical yields were determined by TLC and high-pressure liquid chromatography (HPLC). Tracers showed good localization in inflamed muscle either septic or sterile. The collected data indicates that Pirox and Melox can be used as antiinflammatory imaging agents at 24 and 2 h post injection, respectively.     

Comparative study between chloramine-T and iodogen to prepare radioiodinated etodolac for inflammation imaging

This study describes a fast and efficient method for radiolabeling of etodolac with iodine-125 [¹²⁵I], where both chloramine-T and iodogen were used as oxidizing agents. The labeling reaction was carried out via electrophilic substitution of hydrogen atom with the iodonium cation I⁺. The labeling yield was found to be influenced by different factors such as drug concentration, pH of the reaction mixtures, different oxidizing agents, reaction time, temperature and different organic media. The radiochemical yield (RCY) was determined by TLC system using methylene chloride:ethyl acetate (3:7 v/v) as a developing solvent and by electrophoresis using cellulose acetate moistened with 0.02 M phosphate buffer pH 7. The maximum radiochemical yield of [¹²⁵I]Etodolac (87.7%) was obtained. Labeled etodolac shows a good localization in inflamed muscle. It excretes mainly via kidney and to some via liver.     

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%.     

Radiopharmaceuticals

For studying the metabolism of fatty acids in the heart muscle in-vivo, ω-phenylpenta-decanoic acid (PPA) was labelled with radioiodine to the ortho and para position of the benzene ring with a radiochemical yield of 60%. The products were obtained in a relative isomer distribution of 29%ortho and 71%para radioiodinated PPA. The radiopharmaceutical quality control was performed by sequential radio high pressure liquid chromatography.     

211At and 125I-Labeling of (Hetero)Aryliodonium Ylides: Astatine Wins Again

Despite the growing interest in radioiodine and ²¹¹At-labeled radiopharmaceuticals, the search for radiolabeling reactions has been somewhat neglected, resulting in a limited number of available radiosynthetic strategies. Herein we report a comparative study of nucleophilic ¹²⁵I and ²¹¹At-labeling of aryliodonium ylides. Whereas radioiodination efficiency was low, ²¹¹At-labeling performed efficiently on a broad scope of precursors. The most activated aryliodonium ylides led rapidly to quantitative reactions at room temperature in acetonitrile. For deactivated precursors, heating up to 90 °C in glyme and addition of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as radical scavenger appeared essential to avoid precursor degradation and to achieve high radiochemical yields and molar activity. The approach was applied successfully to the preparation of 4-[²¹¹At]astatophenylalanine (4-APA), an amino acid derivative increasingly studied as radiotherapeutic drug for cancers. This validated aryliodonium ylides as a valuable tool for nucleophilic ²¹¹At-labeling and will complement the short but now growing list of available astatination reactions.     

Labeling of acetaminophen with I-131 and biodistribution in rats

The aim of the present study was to label acetaminophen (APAP) with I-131 and to determine its radiopharmaceutical potential in rats. Acetaminophen was labeled with I-131 using the iodogen method. The radiochemical purity of (131)I-APAP was determined by RTLC and paper electrophoresis. The labeling yield was 94 +/- 4%. The biodistribution studies of the labeled compound (specific activity; 56.60 GBq/mmol) were performed in male Albino Wistar rats. The uptake of (131)I-APAP in some organs were determined at different time after injection to the rats. The radioactivity in each organ was counted and the percentage of injected activity per gram of tissue weight (%ID/g) for each organ and blood was calculated. (131)I-APAP uptake in the lung, liver, kidneys, pancreas, blood, stomach and some brain region, were observed. Thus, (131)I-APAP may be radiopharmaceutical for the imaging of the brain.     

Radioiodination of amitriptyline by isotope exchange

The catalysed isotope exchange method was studied with the aim to elaborate the optimal procedure for labeling of amitriptyline with iodine¹²⁵I. Besides the catalysts published, cuprous salts and ammonium sulphate, a series of transition metal complexes as catalysts were tested at different reaction conditions. The best result (91% radiochemical yield) was achieved with trans-chlorocarbonylbis-(triphenylphosphine) iridium complex (Vaska catalyst) and sonification.     

Comparison study between direct and indirect labeling of estradiol for radioimmunoassay purpose

In the present study, estradiol (E₂) which contains an aromatic phenol ring in its chemical structure was chosen for direct and indirect labeling techniques using ¹²⁵I and chloramine-T oxidation method. In direct technique the hydrogen atom in phenol ring was replaced by a radioiodine atom directly, which in indirect one, histidine methyl ester (HME) was labeled firstly with ¹²⁵I using chloramine-T method then conjugated with E₂. The ¹²⁵I-labeled materials were purified using HPLC technique. The comparison study between the two obtained tracers was carried out in terms of radiochemical purity, binding percent, specific activity, non specific binding, binding displacement, shelf life using a radioimmunoassay (RIA) with specific antibody. The results indicated that indirect iodination of estradiol will cause significant increasing in studied parameters when combined with specific antibody than direct one.     

Preparation of <Superscript>125</Superscript>I-celecoxib with high purity as a possible tumor agent

A preparation of ¹²⁵I-celecoxib is carried out via an electrophilic substitution reaction. The reaction parameters studied were celecoxib concentration, reaction temperature, pH of the reaction mixture and kinds of oxidizing agents in order to obtain a high radiochemical yield of the ¹²⁵I-celecoxib. Using 3.7 MBq of Na¹²⁵I, 150 μg (3.9 mM (mmol/L)) of celecoxib, and 1.6 mM (mmol/L) of chloramine-T (CAT) as oxidant at pH 4 and 60 °C for 15 min a maximum radiochemical yield of ¹²⁵I-celecoxib (65%) was obtained. The labeled compound was separated and purified by means of high pressure liquid chromatography (HPLC). The biological distribution in infected mice indicates the suitability of radioiodinated celecoxib as imaging of tumor.     

Radiochemical separation of antimony by isotopic exchange

Isotopic exchange has been used to develop a simple and rapid procedure for radiochemical separation of antimony. A number of variables which affect the yield were studied and optimised, and antimony yields of 96% were obtained at 30 degrees . Acids and alkalies decrease this yield considerably because they dissolve part of the precipitate. The mode of preparation of the antimony oxide precipitate and the temperature also affect the isotopic exchange. Studies made with radioactive tracers of 14 different elements show contamination of < 1% for most elements. The high contamination with (95)Zr-(95)Nb can be reduced considerably by adding carrier. The simple procedure can be carried out in about 13 min and does not require any special equipment.     

Labeling of atenolol with radioactive iodine-125 using <Emphasis Type="Italic">N</Emphasis>-bromosuccinimide and hydrogen peroxide as oxidizing agents

An adopted method for the preparation of high radiochemical purity ¹²⁵I-atenolol was investigated. Direct radioiodination of atenolol was carried out using N-bromosuccinamide or hydrogen peroxide as an oxidizing agent. The reaction proceeds well within 30 min at room temperature (25 ± 1 °C) and afforded a radiochemical yield up to 97% as pure as ¹²⁵I-atenolol. Different chromatographic techniques (electrophoresis, TLC and HPLC) were used to determine the radiochemical yield and purity of the labeled product. Biodistribution studies were carried out in normal Albino Swiss mice and the results indicate that ¹²⁵I-atenolol can be used safely as myocardial imaging agent.     

Preparation of tagged sodium dodecylbenzenesulfonate of high purity and specific radioactivity

Radioactive tagging of a surface active agent, commonly known as a “surfactant” is described. Sodium dodecylbenzenesulfonate was chosen because it is one of the principal surfactants used in household detergents. To increase the radiochemical yield, the tagged sulfuric acid was concentrated and the minimum amount of non-radioactive 30% fuming sulfuric acid needed to complete the sulfonation determined. The dodecylbenzene used was fractionated from “Neolene-400” using chromatographic methods. The difference in isomers was detected by infrared spectra and refractive indices. Two methods of introducing the radioactive sulfur were employed. The purity of the products obtained was determined from their respective infrared spectra. The final product had a specific radioactivity of 1.24 millicuries per gram of surfactant. Its purity was about 99%. Some experiments using the product are described.     

Radioiodinated phenoxyacetic acid derivatives as potential brain imaging agents. I. Efficient synthesis via trimethylsilyl intermediates

The usefulness of radioiodination via demetallation of aryltrimethylsilanes was demonstrated. The radioiodination reaction was found to be very rapid and the regiospecific incorporation of radioiodine could be carried out with high radiochemical yields and high radiospecific activity. 125I-Labeled dimethylaminoethyl iodophenoxyacetate derivatives (5a--e), dimethylaminoethyl iodophenoxyacetamide derivatives (7a--c), iodophenoxyethyl ethylenediamine derivatives (9,14) and an iodophenoxyethylpiperazine derivative (18) were efficiently synthesized from the corresponding aryltrimethylsilyl intermediates (4a--e, 6a--c, 8, 13, 17) by this method.