Development of an automated production process of [64Cu][Cu (ATSM)] for positron emission tomography imaging and theranostic applications

Cyclotron-produced copper-64 radioisotope tracers offer the possibility to perform both diagnostic investigation by positron emission tomography (PET) and radiotherapy by a theranostic approach with bifunctional chelators. The versatile chemical properties of copper add to the importance of this isotope in medicinal investigation. [⁶⁴Cu][Cu (ATSM)] has shown to be a viable candidate for imaging of tumor hypoxia; a critical tumor microenvironment characteristic that typically signifies tumor progression and resistance to chemo-radiotherapy. Various production and radiosynthesis methods of [⁶⁴Cu][Cu (ATSM)] exist in labs, but usually involved non-standardized equipment with varying production qualities and may not be easily implemented in wider hospital settings. [⁶⁴Cu][Cu (ATSM)] was synthesized on a modified GE TRACERlab FXN automated synthesis module. End-of-synthesis (EOS) molar activity of [⁶⁴Cu][Cu (ATSM)] was 2.2–5.5 Ci/μmol (HPLC), 2.2–2.6 Ci/μmol (ATSM-titration), and 3.0–4.4 Ci/μmol (ICP-MS). Radiochemical purity was determined to be >99% based on radio-HPLC. The final product maintained radiochemical purity after 20 h. We demonstrated a simple and feasible process development and quality control protocols for automated cyclotron production and synthesis of [⁶⁴Cu][Cu (ATSM)] based on commercially distributed standardized synthesis modules suitable for PET imaging and theranostic studies.     

DNA探针的高效标记和哺乳动物细胞转化子的检测

本实验采用随机引物法标记探针DNA.探针DNA加热变性成单链,以单链DNA为模板,六聚脱氧核苷酸为引物,在DNA多聚酶I大片段的作用下进行放射性标记.标记探针的比放射性达10~8cpm/μg DNA以上.放射性底物的掺入率为60%.用该方法标记的人高度重复顺序探针,可以检出微微克水平的阳性分子.与人HeLa S_3细胞DNA转化的小鼠LTK~+细胞DNA打点杂交呈阳性,与未经转化的小鼠LTK~-细胞DNA杂交为阴性,证明小鼠转化细胞中存在HeLa细胞DNA,DNA转化是成功的.     

Synthesis of [18F] 4‐amino‐N‐(3‐chloro‐4‐fluorophenyl)‐N′‐hydroxy‐1,2,5‐oxadiazole‐3‐carboximidamide (IDO5L): a novel potential PET probe for imaging of IDO1 expression

To synthesize ¹⁸F‐labeled positron emission tomography (PET) ligands, reliable labeling techniques inserting ¹⁸F into a target molecule are necessary. The ¹⁸F‐fluorobenzene moiety has been widely utilized in the synthesis of ¹⁸F‐labeled compounds. The present study utilized [¹⁸F]‐labeled aniline as intermediate in [¹⁸F]‐radiolabeling chemistry for the facile radiosynthesis of 4‐amino‐N‐(3‐chloro‐4‐fluorophenyl)‐N′‐hydroxy‐1,2,5‐oxadiazole‐3‐carboximidamide ([¹⁸F]IDO5L) as indoleamine 2,3‐dioxygenase 1 (IDO1) targeted tracer. IDO5L is a highly potent inhibitor of IDO1 with low nanomolar IC₅₀. [¹⁸F]IDO5L was synthesized via coupling [¹⁸F]3‐chloro‐4‐fluoroaniline with carboximidamidoyl chloride as a potential PET probe for imaging IDO1 expression. Under the optimized labeling conditions, chemically and radiochemically pure (>98%) [¹⁸F]IDO5L was obtained with specific radioactivity ranging from 11 to 15 GBq/µmol at the end of synthesis within ~90 min, and the decay‐corrected radiochemical yield was 18.2 ± 2.1% (n = 4).     

Development and characterization of a 99mTc‐labeled Neuropeptide Y short analog with potential application in breast cancer imaging

The aim of this work was to develop and evaluate a ^99mTc‐labeled neuropeptide Y derivative with affinity toward Y1‐receptor. The selected amino acid sequence included nine amino acids derived from the C‐terminal portion of the NPY complemented with the addition of one cysteine‐mercaptoacetic acid moiety to bind the radiometal. Labeling was achieved through the preparation of a 3 + 1 nitrido complex. Physicochemical evaluation, cell uptake, internalization and externalization studies, and competitive assays were performed. Biodistribution experiments were carried out in normal and tumor‐bearing mice. A single product with radiochemical purity >90% and high stability was obtained. In vitro analysis showed specific cellular uptake, IC₅₀ of 73.2 nM, and a high internalization rate (80%). Biodistribution studies showed low blood and renal uptake and combined hepatobiliary and urinary elimination. Preliminary studies in mice bearing induced breast tumors rendered promising uptake values.     

Synthesis and Biological Evaluation of New Quinoxaline Derivatives of ICF01012 as Melanoma-Targeting Probes

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Trifluoromethanesulfonic acid,an alternative solvent medium for the direct electrophilic fluorination of DOPA: new syntheses of 6‐[18F]fluoro‐L‐DOPA and 6‐[18F]fluoro‐D‐DOPA

Previous work from this laboratory has shown that the direct fluorination of 3, 4‐dihydroxy‐phenyl‐L ‐alanine (L ‐DOPA) in anhydrous HF (aHF) or BF₃/HF with F₂ is an efficient method for the synthesis of 6‐fluoro‐L ‐DOPA. Since then, ¹⁸F‐labeled 6‐fluoro‐L ‐DOPA ([¹⁸F]6‐fluoro‐L ‐DOPA) has been used to study presynaptic dopaminergic function in the human brain and to monitor gastrointestinal carcinoid tumors. This work demonstrates that the reactivity and selectivity of F₂ toward L ‐DOPA in CF₃SO₃H is comparable with that in aHF. This new synthetic procedure has led to the production of [¹⁸F]fluoro‐L ‐DOPA and [¹⁸F]fluoro‐D‐DOPA isomers in 17±2% radiochemical yields (decay corrected with respect to [¹⁸F]F₂). The 2‐ and 6‐FDOPA isomers were separated by HPLC and subsequently characterized by ¹⁹F NMR spectroscopy. The corresponding [¹⁸F]‐FDOPA enantiomers have been obtained in clinically useful quantities by a synthetic approach that avoids the use of aHF. Copyright © 2007 John Wiley & Sons, Ltd.     

Etoposide-incorporated tripalmitin nanoparticles with different surface charge: Formulation, characterization, radiolabeling, and biodistribution studies

Etoposide-incorporated tripalmitin nanoparticles with negative (ETN) and positive charge (ETP) were prepared by melt emulsification and high-pressure homogenization techniques. Spray drying of nanoparticles led to free flowing powder with excellent redispersibility. The nanoparticles were characterized by size analysis, zeta potential measurements, and scanning electron microscopy. The mean diameter of ETN and ETP nanoparticles was 391 nm and 362 nm, respectively, and the entrapment efficiency was more than 96%. Radiolabeling of etoposide and nanoparticles was performed with Technetium-99m (99mTc) with high labeling efficiency and in vitro stability. The determination of binding affinity of 99mTc-labeled complexes by diethylene triamine penta acetic acid (DTPA) and cysteine challenge test confirmed low transchelation of 99mTc-labeled complexes and high in vitro stability. Pharmacokinetic data of radiolabeled etoposide, ETN, and ETP nanoparticles in rats reveal that positively charged nanoparticles had high blood concentrations and prolonged blood residence time. Biodistribution studies of 99mTc-labeled complexes were performed after intravenous administration in mice. Both ETN and ETP nanoparticles showed significantly lower uptake by organs of the reticuloendothelial system such as liver and spleen (P < .001) compared with etoposide. The ETP nanoparticles showed a relatively high distribution to bone and brain (14-fold higher than etoposide and ETN at 4 hours postinjection) than ETN nanoparticles. The ETP nanoparticles with long circulating property could be a beneficial delivery system for targeting to tumors by Enhanced Permeability and Retention effect and to brain.     

Exchange radioiodination produces inversion at C‐4 of 1‐(4‐deoxy‐4‐iodo‐β‐D‐xylopyranosyl)‐2‐nitroimidazole

The title compound, 3a , when exchange labeled with ¹²⁵I results in three new labeled products. The major labeled product (84.1%) is 1‐(4‐deoxy‐4‐iodo‐β‐L‐arabinopyranosyl)‐2‐nitroimidazole, 3b , that could result from inversion of configuration at C‐4. Exchange labeling carried out under conditions of kinetic control yielded dramatically different product ratios than thermodynamic equilibrium reactions. Confirmation of these results was established by extensive ¹HNMR spectral analyses. A possible mechanism is presented. Copyright © 2002 John Wiley & Sons, Ltd.     

Synthesis and characterization of scVEGF‐PEG‐[68Ga]NOTA and scVEGF‐PEG‐[68Ga]DOTA PET tracers

Vascular endothelial growth factor (VEGF) signaling via vascular endothelial growth factor receptor 2 (VEGFR‐2) on tumor endothelial cells is a critical driver of tumor angiogenesis. Novel anti‐angiogenic drugs target VEGF/VEGFR‐2 signaling and induce changes in VEGFR‐2 prevalence. To monitor VEGFR‐2 prevalence in the course of treatment, we are evaluating ⁶⁸Ga positron emission tomography imaging agents based on macrocyclic chelators, site‐specifically conjugated via polyethylene glycol (PEG) linkers to engineered VEGFR‐2 ligand, single‐chain (sc) VEGF. The ⁶⁸Ga‐labeling was performed at room temperature with NOTA (2,2′,2′′‐(1,4,7‐triazonane‐1,4,7‐triyl) triacetic acid) conjugates or at 90 °C by using either conventional or microwave heating with NOTA and DOTA (2,2′,2′′,2′′′‐(1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetrayl) tetraacetic acid) conjugates. The fastest (~2 min) and the highest incorporation (>90%) of ⁶⁸Ga into conjugate that resulted in the highest specific radioactivity (~400 MBq/nmol) was obtained with microwave heating of the conjugates. The bioactivity of the NOTA‐ and DOTA‐containing tracers was validated in 3‐D tissue culture model of 293/KDR cells engineered to express high levels of VEGFR‐2. The NOTA‐containing tracer also displayed a rapid accumulation (~ 20 s after intravenous injection) to steady‐state level in xenograft tumor models. A combination of high specific radioactivity and maintenance of functional activity suggests that scVEGF‐PEG‐[⁶⁸ Ga]NOTA and scVEGF‐PEG‐[⁶⁸ Ga]DOTA might be promising tracers for monitoring VEGFR‐2 prevalence and should be further explored. Copyright © 2011 John Wiley & Sons, Ltd.     

Strain-Promoted Catalyst-Free Click Chemistry for Rapid Construction of 64Cu-Labeled PET Imaging Probes

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