Rapid synthesis of C-labeled FK506 for positron emission tomography

The present study describes a rapid synthesis method for labeled [¹¹C]FK506 for positron emission tomography (PET). A one-pot reaction from [¹¹C]CH₃I, involving a Wittig reaction as the key carboncarbon bond formation was developed. The chemical process was accomplished using a designed, fully automated synthetic apparatus, and an injectable solution of [¹¹C]FK506 was obtained in only 34 min from [¹¹C]CH₃I. The decay-corrected radiochemical yield based on [¹¹C]CH₃I was 11.9%, and the specific activity was 39.8 GBq/μmol.     

Synthesis of (S)-N-[methyl-11C]nicotine and its regional distribution in the mouse brain: a potential tracer for visualization of brain nicotinic receptors by positron emission tomography.

A nicotine agonist, 11C-labeled (S)-nicotine, was synthesized by N-methylation of (S)-nornicotine with [11C]-methyl iodide in dimethylformamide-dimethylsulfoxide in order to study nicotinic receptors in the human brain by positron emission tomography. The radiochemical yield of this N-methylation reaction was more than 90% within 5 min. After purification by high performance liquid chromatography the radiochemical purity of the product was more than 99% and the specific radioactivity was 7.4-11.1 GBq/mumol. The regional distribution of (S)-[11C]nicotine in the mouse brain after intravenous injection was compared with that of (R)-[11C]nicotine. After injection of (S)-[11C]nicotine, the regional uptake of radioactivity was in the following order: cortex greater than thalamu approximately hippocampus greater than striatum greater than hypothalamus greater than cerebellum. Moreover, (S)-[11C]nicotine was displaced from the brain by unlabeled (S)-nicotine, but unlabeled (R)-nicotine caused no change in uptake. In contrast, (R)-[11C]nicotine showed a lower brain uptake and lesser regional differences in radioactivity.     

Fluorine-18 and medical imaging: Radiopharmaceuticals for positron emission tomography

Fluorine presents among its radioactive isotopes fluorine-18, that decays with a 109 min half-life and a β⁺ emission, allowing external detection of the two coincident γ photons obtained after annihilation. Production techniques (medical cyclotron), radiochemical reactions for isotope incorporation in radiopharmaceuticals and development of specific detection cameras (positron emission tomographs) allowed development of a vast investigation field in medical imaging.Applications of PET in oncology ([¹⁸F]fluorodeoxyglucose, FDG) largely improved detection and management of cancers; tracer molecules labelled with fluorine-18 also allow fruitful researches in molecular imaging.     

Methylation as a method for synthesis of radiopharmaceuticals for positron emission tomography

The main methods for the production of of ¹¹С-methylating agents and traditional and new perspective routes for their use in the synthesis of radiopharmaceuticals for positron emission tomography were considered.     

Evaluation of scintillators and semiconductor detectors to image three-photon positron annihilation for positron emission tomography

Positron emission tomography (PET) is rapidly becoming the main nuclear imaging modality of the present century. The future of PET instrumentation relies on semiconductor detectors because of their excellent characteristics. Three-photon positron annihilation has been recently investigated as a novel imaging modality, which demands the crucial high energy resolution of semiconductor detector. In this work the evaluation of the NaI(Tl) scintillator and HPGe and CdZTe semiconductor detectors, to construct a simple three-photon positron annihilation scanner has been explored. The effect of detector and scanner size on spatial resolution (FWHM) is discussed. The characteristics: energy resolution versus count rate and point-spread function of the three-photon positron annihilation image profile from triple coincidence measurements were investigated.     

Biological activities of phthalocyanines. XII: Synthesis tumor uptake and biodistribution of 14C-labeled disulfonated and trisulfonated gallium phthalocyanine in C3H mice

The biodistribution and metabolism of 14C-labeled disulfonated and trisulfonated gallium phthalocyanine (Ga-PcS) was studied in radiation-induced fibrosarcoma tumor-bearing C3H mice. The [14C]Ga-PcS compounds were prepared via the condensation of [14C]phthalic acid and sulfophthalic acid in the presence of gallium chloride and characterized by their spectroscopic and chromatographic properties. The tissue concentrations of the dyes was measured by scintillation counting of the 14C and by extraction and fluorescence measurements. Elevated dye levels were found in the liver, lungs, kidneys and spleen as well as in the tumor. Lower sulfonation of Ga-PcS favored liver and spleen uptake whereas higher dye sulfonation resulted in greater kidney uptake. Both dyes showed high tumor uptake with peak concentrations exceeding those of most tissues except for the liver in the case of Ga-PcS2. The highest tumor uptake was observed with Ga-PcS3. Both dyes were slowly excreted from the body. The liver-feces pathway was favored in the case of Ga-PcS2 with high activities persisting in the liver, even after 21 days. The Ga-PcS3 was preferentially excreted via the kidney-urine pathway. High performance liquid chromatography analysis of the liver and tumor extracts of [14C]Ga-PcS3-treated animals did not reveal desulfonation of the dye. However, urine analysis showed the presence of radioactive metabolites lacking the characteristic phthalocyanine absorption.     

Synthesis of 99m TcN(IPDTC)2 and its biodistribution in mice

In order to seek a new class of brain perfusion imaging agent containing[ ^99m TcN]²+ core, the bis(N-isopropyl dithiocarbamato)nitrido technetium-99m complex [ ^99m TcN(IPDTC)₂ ] (IPDTC:N-isopropyldithiocarbamato) has been synthesized through a simple and efficient method,which can be utilized for the preparation of a radiopharmaceutical througha lyophilized formulation. The radiochemical purity of the complex was over90% determined by thin layer chromatography. No decomposition of the complexwas observed at room temperature over a period of 12 hours. Its partitioncoefficient indicated that it was a good lipophilic complex. Biodistributionin mice demonstrated that the complex was significantly retained into thebrain. The brain uptake (ID%/g) was 3.90, 2.67 and 1.54 and the brain/bloodratios were 1.26, 1.06 and 0.85 at 5, 30 and 60-minute post-injection, respectively.The results showed that the complex may lead to a further development of theradiopharmaceutical as a brain perfusion tracer.     

中枢多巴胺系统正电子发射计算机断层扫描显像剂的研究进展

中枢多巴胺系统与多种神经行为障碍的病理生理学有关。一直以来,多巴胺系统正电子发射计算机断层扫描(PET)成像在研究活体大脑中多巴胺生物化学过程上有着重要价值。PET成像的基础是¹¹C、¹⁸F等发射正电子的放射性核素标记的显像剂,这些显像剂通过与多巴胺神经系统不同的靶点特异性结合从而反映多巴胺合成、囊泡储存、突触释放和受体结合以及再摄取过程,推动神经病学、精神病学、药物滥用和成瘾以及药物开发的研究进展。本文综述了以氨基酸脱羧酶、多巴胺转运体、多巴胺受体以及囊泡单胺转运体为靶点的¹¹C、¹⁸F标记的PET显像剂的研究进展。     

中枢多巴胺系统正电子发射计算机断层扫描显像剂的研究进展

中枢多巴胺系统与多种神经行为障碍的病理生理学有关。一直以来,多巴胺系统正电子发射计算机断层扫描(PET)成像在研究活体大脑中多巴胺生物化学过程上有着重要价值。PET成像的基础是¹¹C、¹⁸F等发射正电子的放射性核素标记的显像剂,这些显像剂通过与多巴胺神经系统不同的靶点特异性结合从而反映多巴胺合成、囊泡储存、突触释放和受体结合以及再摄取过程,推动神经病学、精神病学、药物滥用和成瘾以及药物开发的研究进展。本文综述了以氨基酸脱羧酶、多巴胺转运体、多巴胺受体以及囊泡单胺转运体为靶点的¹¹C、¹⁸F标记的PET显像剂的研究进展。     

Synthesis of analogues of (-)-cytisine for in vivo studies of nicotinic receptors using positron emission tomography

[formula: see text] 9-Substituted analogues of (-)-cytisine were synthesized in high yields via palladium-mediated couplings of either 9-(-)-bromocytisine and organostannanes or 9-(-)-trimethylstannylcytisine and fluorobromobenzene. The protection of the amine with a nitroso group and the use of PdCl2(PPh3)2 to carry out the Stille reaction allowed the rapid synthesis of 9-(4'-[18F]fluorophenyl)cytisine (18F: t1/2 = 109.7 min), a new promising radioligand (radiochemical yield: 10% from [18F]KF, 150 min, four steps) for positron emission tomography studies of alpha 4 beta 2 nicotinic receptors.     

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 %.     

Synthesis of 11C, 18F, 15O, and 13N radiolabels for positron emission tomography

Positron emission tomography (PET) is a powerful and rapidly developing area of molecular imaging that is used to study and visualize human physiology by the detection of positron-emitting radiopharmaceuticals. Information about metabolism, receptor/enzyme function, and biochemical mechanisms in living tissue can be obtained directly from PET experiments. Unlike magnetic resonance imaging (MRI) or computerized tomography (CT), which mainly provide detailed anatomical images, PET can measure chemical changes that occur before macroscopic anatomical signs of a disease are observed. PET is emerging as a revolutionary method for measuring body function and tailoring disease treatment in living subjects. The development of synthetic strategies for the synthesis of new positron-emitting molecules is, however, not trivial. This Review highlights key aspects of the synthesis of PET radiotracers with the short-lived positron-emitting radionuclides (11)C, (18)F, (15)O, and (13)N, with emphasis on the most recent strategies.     

Toward [18F]-labeled aryltrifluoroborate radiotracers: in vivo positron emission tomography imaging of stable aryltrifluoroborate clearance in mice

The use of a boronic ester as a captor of aqueous [(18)F]-fluoride has been previously suggested as a means of labeling biomolecules in one step for positron emission tomography (PET) imaging. For this approach to be seriously considered, the [(18)F]-labeled trifluoroborate should be humorally stable such that it neither leaches free [(18)F]-fluoride to the bone nor accumulates therein. Herein, we have synthesized a biotinylated boronic ester that is converted to the corresponding trifluoroborate salt in the presence of aqueous [(18)F]-fluoride. In keeping with its in vitro aqueous kinetic stability at pH 7.5, the trifluoroborate appears to clear in vivo quite rapidly to the bladder as the stable trifluoroborate salt with no detectable leaching of free [(18)F]-fluoride to the bone. When this labeled biotin is preincubated with avidin, the pharmacokinetic clearance of the resulting complex is visibly altered. This work validates initial claims that boronic esters are potentially useful as readily labeled precursors to [(18)F]-PET reagents.     

Efficient bifunctional gallium-68 chelators for positron emission tomography: tris(hydroxypyridinone) ligands

A new tripodal tris(hydroxypyridinone) bifunctional chelator for gallium allows easy production of (68)Ga-labelled proteins rapidly under mild conditions in high yields at exceptionally high specific activity and low concentration.     

A practical guide to the construction of radiometallated bioconjugates for positron emission tomography

Positron emission tomography (PET) has become a vital imaging modality in the diagnosis and treatment of disease, most notably cancer. A wide array of small molecule PET radiotracers have been developed that employ the short half-life radionuclides (11)C, (13)N, (15)O, and (18)F. However, PET radiopharmaceuticals based on biomolecular targeting vectors have been the subject of dramatically increased research in both the laboratory and the clinic. Typically based on antibodies, oligopeptides, or oligonucleotides, these tracers have longer biological half-lives than their small molecule counterparts and thus require labeling with radionuclides with longer, complementary radioactive half-lives, such as the metallic isotopes (64)Cu, (68)Ga, (86)Y, and (89)Zr. Each bioconjugate radiopharmaceutical has four component parts: biomolecular vector, radiometal, chelator, and covalent link between chelator and biomolecule. With the exception of the radiometal, a tremendous variety of choices exists for each of these pieces, and a plethora of different chelation, conjugation, and radiometallation strategies have been utilized to create agents ranging from (68)Ga-labeled pentapeptides to (89)Zr-labeled monoclonal antibodies. Herein, the authors present a practical guide to the construction of radiometal-based PET bioconjugates, in which the design choices and synthetic details of a wide range of biomolecular tracers from the literature are collected in a single reference. In assembling this information, the authors hope both to illuminate the diverse methods employed in the synthesis of these agents and also to create a useful reference for molecular imaging researchers both experienced and new to the field.