Minimizing liver uptake of cationic ^(99m)Tc radiotracers with ether and crown ether functional groups

Ischemia-related diseases,particularly coronary artery disease(CAD),account for the majority of deaths worldwide.Myocardial ischemia is a serious condition and the delay in reperfusion of ischemic tissues can be life-threatening.This is particular true in the aged population.Rapid and accurate early detection of myocardial ischemia is highly desirable so that various therapeutic regiments can be given before irreversible myocardial damage occurs.Myocardial perfusion imaging with radiotracers is an integral component in evaluations of patients with known or suspected CAD. 99m Tc-Sestamibi and 99m Tc-Tetrofosmin are commercial radiopharmaceuticals currently available for myocardial perfusion imaging.Despite their widespread clinical applications,both 99m Tc-Sestamibi and 99m Tc-Tetrofosmin do not meet the requirements of an ideal perfusion imaging agent,largely due to their high liver uptake.The intense liver uptake makes it difficultto interpret the heart activity in the inferior and left ventricular wall.Photon scattering from the high liver radioactivity accumulation remains a significant challenge for diagnosis of heart diseases.This review will summarize the most recent research efforts to minimize the liver uptake of cationic 99m Tc radiotracers by using ether and crown ether-containing chelators. Fast liver clearance will shorten the duration of imaging protocols(<30 min post-injection) ,and allow for early acquisition of heart images with high quality. Improvement of heart/liver ratio may permit better detection of the presence and extent of coronary artery disease.Identification of such a new radiotracer that allows for the improved noninvasive assessment of myocardial perfusion would be of considerable benefit in treatment of patients with suspected CAD.

Evaluation of 64Cu-DOTA- and 64Cu-CBTE2A-Galectin-3 Peptide as a PET Radiotracer for breast Carcinoma

Galectin-3 (Gal-3) is a β-galactosidase binding protein that modulates various cellular processes including cell adhesion, and metastasis. We evaluated the tumor targeting and imaging properties of a galectin-3 binding peptide originally selected from bacteriophage display, in a mouse model of human breast carcinoma expressing galectin-3. A galectin-3 binding peptide, ANTPCGPYTHDCPVKR, was synthesized with a Gly-Ser-Gly (GSG) spacer and 1,4,7,10, tetraazacyclododecane-N,N’,N’’,N’’’-tetracetic acid (DOTA) or 4,11-bis(carboxymethyl)-1,4,8,11 tetrazabicyclo[6.6.2]hexadecane 4,11-diacetic acid (CB-TE2A), and radiolabeled with 64Cu. The synthesized peptides 64Cu-DO3A-(GSG)-ANTPCGPYTHDCPVKR (64Cu-DO3A- pep) and 64Cu-CB-TE2A-(GSG)-ANTPCGPYTHDCPVKR(64Cu-CB-TE2A-pep) demonstrated an IC50 value of 97 ± 6.7 nM and 130 ± 10.2 nM, respectively, to cultured MDA-MB-435 breast carcinoma cells in vitro in a competitive displacement binding study. The tumor tissue uptake in SCID mice bearing MDA-MB-435 tumors was 1.2 ± 0.18 %ID/g (64Cu-DO3A-pep) and 0.85 ± 0.0.9 %ID/g (64Cu-CB-TE2A-pep) at 30 min, respectively. While liver retention was moderate with both radiolabeled peptides the kidney retention was observed to be high. Radiation dose delivered to the tumor was estimated to be 42 mGy/mCi and 129 mGy/ mCi with CB-TE2A and DO3A peptides, respectively. Imaging studies demonstrated tumor uptake with both 64Cu-DO3A- and 64Cu-CB-TE2A-(GSG)-ANTPCGPYTHDCPVKR after 2 h post injection. These studies suggest that gal-3 binding peptide could be developed into a PET imaging agent for galectin-3-expressing breast tumors.

Radiotracer Investigation of the Effect of Impeller Type on Mixing in Industrial Process Simulator

Radiotracer technology has been applied in industry for the investigation of process performance, online monitoring of conditions of process units, troubleshooting and diagnosing anomalies including mixing conditions in continuous stirred tank reactors. In this study, radiotracer methodology was used to carry out investigation on a laboratory water flow rig which serves as simulator of industrial processes. The aims of the investigation were to assess: i) the effect of impeller type on mixing and ii) the fluid dynamics of the water in the vessels since both the vessels and the impellers were redesigned and reconstructed. Four similar vessels in series circuit with different impeller configurations were investigated. Tank 1 has 1 axial impeller, Tank 2 has 2 axial impellers, Tank 3 has 2 radial impellers and Tank 4 has no impeller. The data were collected by introducing 8 mCi liquid technetium-99 m at the inlet stream of the vessels and the gamma signal was detected with thallium activated NaI detector placed at the outlet of the vessels. Residence Time Distribution (RTD) curves for the outlet tracer concentration were generated from which the Mean Residence Time (MRT) and the variance were calculated by the method of moments. The extent of material mixing in the vessels was inferred from the variances and the fluid dynamics was obtained by modeling. The extent of mixing was highest in Tank 2 followed by Tank 3, and Tank 4 gave the poorest mixing. The outlet response curves were fitted with mathematical models using DTS pro and “RTD Software”. The best fit for Tanks 2, 3 and 4 was Perfect Mixers in Series with Exchange (PMSE) model while Perfect Mixers in Series with Recycle (PMSR) model best described the fluid dynamics of the material in Tank 1.

Radiotracers and Nucleonic Control Systems Applied in Industry—Polish Case

Nuclear and radiation technologies play an important role in Polish power sector, oil industry and mining sector, starting from fossil fuels exploitation, their transport and distribution and finally power generation. Application of environmental isotopes, stable and radioactive, in ground water monitoring in the vicinity of open cast lignite mine, and radon monitor applied for miner’s safety in deep coal mines and nucleonic control systems for ash in coal quality control is often used in mining industry. Other applications of nuclear techniques reviewed, concern the oil industry, oil field recovery, transportation pipelines and refineries. Finally, the application of beta radiation-based gauges for air borne fly ash monitoring and radiation technology for flue gas treatment are the examples of using this technique in power sector equipped with coal and oil fired boilers [1]. The radiotracers techniques were used also in glass industry (determination and optimization parameters of the furnaces), cement industry (test of aggregates for the production of cement and optimization media transport in pipelines), metallurgy of Cu, Pb, Zn (investigation of pyrometallurgy processes and new techniques), cellulose industry, environmental and (mainly hydrological) research etc. [2]. The article is brief review of present status of radiotracer and nucleonic gauges techniques as applied to polish industry.

Production of Gallium-68 with Medium to Low Energy Cyclotrons: What Opportunities for the Development of PET Radiotracers in Senegal?

This study focuses on the development possibilities of radiotracers used in PET in Senegal. This is a literature review that develops the production of 68-Gallium (68Ga[Ga]) via a medium to low energy cyclotron. It shows the possibility of producing 68Ga[Ga] with a simple production reaction using a target of 68Zn. This reaction provides high production yields, at the end of the bombardment (EOB), reaching up to 80 times the activity of a generator. PET imaging may offer better sensitivity and spatial resolution compared to SPECT which is currently used in Senegal. The acquisition of this type of medium to low energy accelerator in Senegal may constitute an important phase in the development of radiotracers with the objective of installing a PET imaging. However, solutions must be provided to minimize the presence of isotopic impurities.

Difluorocarbene-derived rapid late-stage trifluoromethylation of 5-iodotriazoles for the synthesis of^(18)F-labeled radiotracers

Difluorocarbene has emerged as a valuable intermediate to synthesize fluorides.However,difluorocarbene-derived synthesis of^(19)F/^(18)F-trifluoromethyl triazoles has not been explored.Herein,we reported the Cu(I)-promoted difluorocarbene-derived^(19)F/^(18)F-trifluoromethylation of iodotriazoles using KF/K^(18)F as the fluorine source.This approach rapidly generated a wide range of 5-trifluoromethyl-1,2,3-triazoles in good yields showing high functional group compatibility.The reaction was effective for late-stage functionalization of bioactive molecules and^(18)F-trifluoromethylation of iodotriazoles.This work provides a practical synthetic methodology for the development of triazole drugs and^(18)F-radiotracers for positron emission tomography.

Development of ^(18)F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Positron emission tomography （PET） is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. Fluorine-18 is a radionuclide routinely used in the radiolabeling of neuroreceptor ligands for PET because of its favorable half-life of 109.8 min. The delivery of such radiotracers into the brain provides images of transport, metabolic, and neurotransmission processes on the molecular level. After a short introduction into the principles of PET, this review mainly focuses on the strategy of radiotracer development bridging from basic science to biomedical application. Successful radiotracer design as described here provides molecular probes which not only are useful for imaging of human brain diseases, but also allow molecular neuroreceptor imaging studies in various small-animal models of disease, including genetically- engineered animals. Furthermore, they provide a powerful tool for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, to investigate pathophysiology, to discover potential drug candidates, and to evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo.

Synthesis and Preliminary Evaluation of 1-[^18F]Fluoro-1-deoxy-2,5-anhydro-D-mannitol as a PET Radiotracer for Breast Cancer Imaging

1-[^18F]Fluoro-l-deoxy-2,5-anhydro-D-mannitol （3, ^18F-FDAM） has been synthesized in 6 steps starting from 2,5-anhydro-D-mannitol （2,5-AM） and evaluated as a new radiotracer for PET imaging of MCF-7 breast tumor. The result of PET imaging study showed that 3 displayed a slightly higher uptake by breast tumor in comparison with the normal breast tissue, implying the possibility of development of PET radiotraeers based on targeting fructose transporters.

Positron-emission tomography for hepatocellular carcinoma:Current status and future prospects

Hepatocellular carcinoma(HCC)is one of the leading causes of cancer mortality worldwide.Various imaging modalities provide important information about HCC for its clinical management.Since positron-emission tomography(PET)or PET-computed tomography was introduced to the oncologic setting,it has played crucial roles in detecting,distinguishing,accurately staging,and evaluating local,residual,and recurrent HCC.PET imaging visualizes tissue metabolic information that is closely associated with treatment.Dynamic PET imaging and dual-tracer have emerged as complementary techniques that aid in various aspects of HCC diagnosis.The advent of new radiotracers and the development of immuno-PET and PET-magnetic resonance imaging have improved the ability to detect lesions and have made great progress in treatment surveillance.The current PET diagnostic capabilities for HCC and the supplementary techniques are reviewed herein.

Tumor targeting of HPMA copolymer conjugates containing sulfadiazine groups

To develop new tumor targeting macromolecular conjugates,poly（HPMA）-SD-APMA-DTPA（HPMA：N-（2-hydroxypropyl）- methacrylamide;APMA：N-（3-ammopropyl）methacrylamide;DTPA：diethylenetriaminepentaacetic acid;SD：sulfadiazine） was synthesized and characterized.The poly（HPMA）-SD-DTPA conjugates were radiolabeled with the radionuclide ^（99m）Tc and tested for uptake by cultured H22 cells in vitro.DTPA-^（99m）Tc（radiotracer 1） and poly（HPMA）-DTPA-^（99m）Tc（radiotracer 2） were also synthesized and characterized for comparison.The uptake of poly（HPMA）-SD-DTPA-^（99m）Tc（radiotracer 3,34.76%） was significantly higher than that of poly（HPMA）-DTPA-^（99m）Tc（16.40%）,indicating that uptake of the poly（HPMA）-SD-DTPA-^（99m）T was active binding.The uptake of poly（HPMA）-DTPA-^（99m）Tc was significantly higher than that of DTPA-^（99m）Tc（2.98%）, suggesting that uptake of the poly（HPMA）-DTPA-^（99m）T was passive binding.The data suggest that the poly（HPMA）-SDAPMA -DTPA conjugates might be useful as tumor targeting macromolecular conjugates.

Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease

Although the epigenetic regulatory protein histone deacetylase 6(HDAC6)has been recently implicated in the etiology of Alzheimer’s disease(AD),little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD.Here,we performed positron emission tomography(PET)imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD.We first developed[^(18)F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high specificity to HDAC6.PET studies of[^(18)F]PB118 in 5xFAD mice showed significantly increased radioactivity in the brain compared to WT animals,with more pronounced changes identified in the cortex and hippocampus.The translatability of this radiotracer for AD in a potential human use was supported by additional studies,including similar uptake profiles in non-human primates,an increase of HDAC6 in ADrelated human postmortem hippocampal tissues by Western blotting protein analysis,and our ex vivo histopathological analysis of HDAC6 in postmortem brain tissues of our animals.Collectively,our findings show that HDAC6 may lead to AD by mechanisms that tend to affect brain regions particularly susceptible to AD through an association with amyloid pathology.

Synthesis and characterization of the two enantiomers of a chiral sigma-1 receptor radioligand:(S)-(+)-and(R)-(-)-[^(18)F]FBFP

Racemic[^(18)F]FBFP([^(18)F]1)proved to be a potentσ_(1) receptor radiotracer with superior imaging properties.The pure enantiomers of unlabeled compounds(S)-and(R)-1 and the corresponding iodonium ylide precursors were synthesized and characterized.The two enantiomers(S)-1 and(R)-1 exhibited comparable high affinity forσ_(1) receptors and selectivity overσ_(2) receptors.The Ca^(2+) fluorescence assay indicated that(R)-1 behaved as an antagonist and(S)-1 as an agonist forσ_(1) receptors.The ^(18)F-labeled enantiomers(S)-and(R)-[^(18)F]1 were obtained in>99%enantiomeric purity from the corresponding enantiopure iodonium ylide precursors with radiochemical yield of 24.4%±2.6%and molar activity of 86–214 GBq/μmol.In ICR mice both(S)-and(R)-[^(18)F]1displayed comparable high brain uptake,brain-to-blood ratio,in vivo stability and binding specificity in the brain and peripheral organs.In micro-positron emission tomography(PET)imaging studies in rats,(S)-[^(18)F]1 exhibited faster clearance from the brain than(R)-[^(18)F]1,indicating different brain kinetics of the two enantiomers.Both(S)-and(R)-[^(18)F]1 warrant further evaluation in primates to translate a single enantiomer with more suitable kinetics for imaging theσ_(1) receptors in humans.

Interventional Radionuclide Therapy of Hepatocellular Carcinoma： Assessment of Intratumoral Retention of HPMA Copolymers

To develop new radiopharmaceuticals for the interventional radionuclide therapy of recurrent hepatocellular carcinoma, poly（HPMA）-APMA-DTPA[HPMA=N-（2-hydroxypropyl） methacrylamide; APMA=N-（3-aminopropyl）methacrylamide; DTPA=diethylenetriaminepentaacetic acidl was synthesized by free radical precipitation polymerization in acetone/dimethylsulfoxide with N,N＇-azobis（isobutyronitrile） as the initiator. The copolymers were characterized with nuclear magnetic resonance（NMR） spectroscopy and gel permeation chromatography（GPC, Mn=2.2xl04, Mw/Mn=l.38）. Subsequently, poly（HPMA）-APMA-DTPA was conjugated with 99mTC radionuclide. Prolonged retention of poly（HPMA）-APMA-DTPA conjugate within the tumor tissues was demonstrated by single-photon emission computed tomography computed tomography（SPECT-CT） at 1, 2, 4 and 24 h following intra-tumoral injection of the conjugate to hepatocellular carcinoma xenografts in mice. DTPA-99mTc was also synthesized and characterized for comparison. The data suggest that the poly（HPMA）-APMA-DTPA conjugates might be useful for the interventional radionuclide therapy of recurrent hepatocellular carcinoma in humans.