132 research outputs found

    Optimized labeling of NOTA-conjugated octreotide with F-18

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    We recently reported a facile method based on the chelation of [18F]aluminum fluoride (Al18F) by NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid). Here, we present a further optimization of the 18F labeling of NOTA-octreotide (IMP466). Octreotide was conjugated with the NOTA chelate and was labeled with 18F in a two-step, one-pot method. The labeling procedure was optimized with regard to the labeling buffer, ionic strength, peptide concentration, and temperature. Radiochemical yield, specific activity, in vitro stability, and receptor affinity were determined. Biodistribution of 18F-IMP466 was studied in AR42J tumor-bearing mice. In addition, microPET/CT images were acquired. IMP466 was labeled with Al18F in a single step with 97% yield in the presence of 80% (v/v) acetonitrile or ethanol. The labeled product was purified by HPLC to remove unlabeled peptide and unbound Al18F. The radiolabeling, including purification, was performed for 45 min. Specific activities of 48,000 GBq/mmol could be obtained. 18F-IMP466 showed a high tumor uptake and excellent tumor-to-blood ratios at 2 h post-injection. In addition, the low bone uptake indicated that the Al18F–NOTA complex was stable in vivo. PET/CT scans revealed excellent tumor delineation and specific accumulation in the tumor. Uptake in receptor-negative organs was low. NOTA-octreotide could be labeled with 18F in quantitative yields using a rapid two-step, one-pot, method. The compound was stable in vivo and showed rapid accretion in SSTR2-receptor-expressing AR42J tumors in nude mice. This method can be used to label other NOTA-conjugated compounds such as RGD peptides, GRPR-binding peptides, and Affibody molecules with 18F

    Technetium Nitrido-Peroxo Complexes: An Unexplored Class of Coordination Compounds

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    The purpose of this work was to further expand the chemistry of mixed technetium nitrido-peroxo complexes, a still poorly explored class of compounds containing the Tc(VII) moiety, [99gTc][Tc(N)(O2)2]. A number of novel complexes of the formula [99gTc][Tc(N)(O2)2(L)] with bidentate ligands (L) (where L = deprotonated alanine, glycine, proline) were prepared by reacting a solution of nitrido-technetic(VI) acid with L in the presence of a source of H2O2. Alternatively, the complex [99gTc][Tc(N)(O2)2X]− (X = Cl, Br) was used as a precursor for substitution reactions where the halogenide ion was replaced by the bidentate ligand. The new complexes were characterized by elemental analysis and mass spectroscopy. The preparation of the analogous [99mTc][Tc(N)(O2)2] moiety, radiolabeled with the metastable isomer Tc-99m, was also studied at a no-carrier-added level, using S-methyl-N-methyl-dithiocarbazate as the donor of the nitrido nitrogen atoms

    Methodological advancements in microfluidic and carbonylation PET radiochemistry

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    Along with the progress of PET as a powerful imaging tool in medicine, there has been increasing demand for new labeling methods. The main aim of this PhD dissertation was to develop novel labeling methodologies using the positron emitter carbon-11. Advancements within the field of palladium-mediated carbonylation reaction are discussed in the first part of the thesis. Paper I describes the development of a Pd-ligand complex where [11C]carbon monoxide (11CO) is efficiently trapped and incorporated as a part of the CO- insertion procedure. The consequent carbonylation reaction proceeds smoothly in good and reproducible yields using aryl halides or triflates as substrates. As a proof of concept, the utility of the protocol was applied to the synthesis of a candidate radioligand for the histamine type-3 receptor. The same protocol was further improved using microwave heating in paper II. An improved yield was observed in the 11C-aminocarbonylation of electron deficient aryl halides and even allowing for the use of an aryl chloride as substrate. Moreover, high yields for hydroxy- and alkoxycarbonylation were obtained when efficient microwave-energy absorbent nucleophiles, such as water and alcohol, were utilized as co-solvents. In paper III, an efficient and convenient carbonylative approach for the direct synthesis of 11C-labeled aryl methyl ketones from aryl halides is presented, employing [11C]methyl iodide (11CH3I) as the radioactive precursor under Co2(CO)8-mediated conditions. A total of ten model (hetero)aryl methyl ketones were obtained in a 22-63% decay-corrected radiochemical yield, based on radioactivity in the solution at the end of synthesis. The increasing demand of rapid labeling procedures has stimulated the development of emerging technologies such as microfluidics for more flexible and efficient radioligand supply. To this end, in the second part of the thesis, microfluidic-assisted radiochemistry was evaluated for the labeling with fluorine-18 and carbon-11. Firstly, in paper IV, a commercially available microfluidic (MF) platform was evaluated using the two-step preparation of 18F-fluorobenzyl amines via a reductive amination reaction. The microfluidic apparatus allowed for rapid parameter optimization and was also applied preparatively to produce adequate radioactivities for PET applications. Finally, in paper V, a novel gas-liquid segmented microfluidic platform was developed. The large gas-to-liquid interfacial area generated by the segmented approach facilitated the 11CO insertion even while less reactive Pd-ligand species were applied. The Pd- mediated 11C-carbonylation reaction proceeded smoothly on this platform and good to excellent radiochemical yields were observed. Twelve compounds were successfully radiolabeled in a RCY range of 41-99%, including the well establiched D2 receptor radioligands [11C]raclopride and [11C]FLB 457

    Highlight selection of radiochemistry and radiopharmacy developments by editorial board

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    BackgroundThe Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development.ResultsThis commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals.ConclusionTrends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry

    Synthesis and radiofluorination of putative NMDA receptor ligands

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    In the course of this work on the synthesis of radioligands for the NMDA receptor the authentic standards and labeling precursors of four compounds with an amidine structure was performed. Synthesis of the precursors followed reaction conditions given in the literature and was successful. The imidoesters used for the synthesis were obtained from their nitriles in a Pinner synthesis, while 2-hydroxybenzylamine was synthesized in a reduction of 2-hydroxybenzonitrile using borane as a reducing agent. After a coupling reaction of the amine and the imidoester in DMF using triethylamine as base the precursors were obtained in good yields and purified by crystallization from methanol. The cyclic standard compound was synthesized directly from 2-(bromo-methyl) benzonitrile and 2-hydroxybenzylamine in a ring closing reaction. Similar to the other precursors, crystallization from methanol produced a pure compound. The authentic standards were synthesized starting from salicylaldehyde. In a four step synthesis the desired ortho fluoroethoxybenzylamine was obtained in good yield. Coupling of the amine with the respective imidoester or in the case of the cyclic compound 2-(bromomethyl)-benzonitrile gave the desired product which was then purified by column chromatography or by crystallization from ethanol and water. For the labeling procedure 1-bromo-2-[18F]fluoroethane was synthesized following a previously published pathway starting from 1,2-dibromoethane. An alternative route of radiosynthesis for this prosthetic group was tested using ethyleneglycole-1,2-ditosylate. The labeling reaction was performed on one of the precursors testing both DMF and DMSO as solvents and using NaOH as base. Yields of N-(2-fluoroethoxybenzyl)-cinnamamidine were about 78 % at 80 °C after 30 minutes in DMSO. The desired product can now be synthesized in sufficient yields for in vitro and in vivo evaluation studies. Labeling on the cyclic precursor was attempted utilizing DMSO as solvent, but no product could be found

    Strategies for Site-Specific Radiolabeling of Peptides and Proteins

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    Although anatomical imaging modalities (X-ray, computed tomography (CT), magnetic resonance imaging (MRI)) still have a higher spatial resolution (0.1–1 mm) than molecular imaging modalities (single-photon emission computed tomography (SPECT), positron emission tomography (PET), optical imaging (OI)), the advantage of molecular imaging is that it can detect molecular and cellular changes at the onset of a disease before it leads to morphological tissue changes, which can be detected by anatomical imaging. During the last decades, noninvasive diagnostic imaging has encountered a rapid growth due to the development of dedicated imaging equipment for preclinical animal studies. In addition, the introduction of multimodality imaging (PET/CT, SPECT/CT, PET/MRI) which combines high-resolution conventional anatomical imaging with high sensitivity of tracer-based molecular imaging techniques has led to successful accomplishments in this exciting field. In this book chapter, we will focus on chemical synthesis techniques for site-specific incorporation of radionuclide chelators. Subsequently, radiolabeling based on complexation of a radionuclide with a chelator will be discussed, with focus on: diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-triacetic acid (NOTA), hexa-histidine (His-tag), and 6-hydrazinonicotinic acid (HYNIC) that allow the production of peptides labeled with 18F, 68Ga, 99mTc, and 111In – the currently most widely used isotopes
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