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One of the hallmarks of cancer is increased cell proliferation. Measurements of cell proliferation by estimation of DNA synthesis with several radiolabeled nucleosides have been tested to assess tumor growth. Deoxycytidine can be phosphorylated by deoxycytidine kinase (dCK) and is incorporated into DNA. This study evaluated a radiofluorinated deoxycytidine analog, 5-[18F]fluoro-2′-deoxycytidine ([18F]FdCyd), as a proliferation probe and compared it with 5-[18F]fluoro-2′-deoxyuridine ([18F]FdUrd), 3′-deoxy-3'-[18F]fluorothymidine ([18F]FLT), and [18F]fluorodeoxyglucose ([18F]FDG) in a tumor-bearing mouse model. [18F]FdCyd was synthesized from two precursors by direct electrophilic substitution. The serum stability and partition coefficient of [18F]FdCyd were evaluated in vitro. Positron emission topography (PET) imaging of Lewis lung carcinoma (LLC)-bearing mice with [18F]FdCyd, [18F]FdUrd, [18F]FLT, and [18F]FDG were evaluated. [18F]FdCyd was stable in mouse serum and normal saline for up to 4 h. With all radiotracers except [18F]FLT, PET can clearly delineate the tumor lesion. [18F]FdCyd and [18F]FdUrd showed high accumulation in the liver and kidney. The SUV and tumor-to-muscle (T/M) ratios derived from PET imaging of the radiotracers were [18F]FDG > [18F]FdCyd > [18F]FdUrd > [18F]FLT. Selective retention in tumors with a favorable tumor/muscle ratio makes [18F]FdCyd a protential candidate for further investigation as a proliferation imaging agent.

Introduction Multiple peptide receptors are co-expressed in many types of cancers. Arg-Gly-Asp (RGD) and GE11 peptides specifically target integrin αVβ3 and EGFR, respectively. Recently, we designed and synthesized a heterodimer peptide NOTA-c(RGDyK)-GE11 (NOTA-RGD-GE11). The aim of this study was to investigate the characteristics of NOTA-RGD-GE11 for dual receptor imaging. Methods NOTA-RGD-GE11 heterodimer was labelled with 68Ga. The dual receptor binding affinity was investigated by antibody competition binding assay. The in vitro and in vivo characteristics of [68Ga]Ga-NOTA-RGD-GE11 were investigated and compared with that of monomeric peptides [68Ga]Ga-NOTA-RGD and [68Ga]Ga-NOTA-GE11. Results NOTA-RGD-GE11 had binding affinities with both integrin αVβ3 and EGFR. The dual receptor targeting property of [68Ga]Ga-NOTA-RGD-GE11 was validated by blocking studies in a NCI-H292 tumour model. [68Ga]Ga-NOTA-RGD-GE11 showed higher tumour uptake than [68Ga]Ga-NOTA-RGD and [68Ga]Ga-NOTA-GE11 in biodistribution and PET/CT imaging studies. Conclusion The dual receptor targeting and enhanced tumour uptake of [68Ga]Ga-NOTA-RGD-GE11 warrant its further investigation for dual integrin αVβ3 and EGFR-targeted tumour imaging.

[123I]IBZM is used widely for in vivo imaging of D2 receptors in human brain and shows relatively fast kinetics and a greater susceptibility to synaptic dopamine release than other single-photon emission computed tomography (SPECT) radioligands. A reliable and reversed-phase HPLC method using UV/VIS and radiometric detectors has been developed for qualitative analysis of BZM and IBZM and radiochemical purity in [123I]IBZM preparations. The method uses gradient elution on a Zorbax XDB C-18 column with a mobile phase that consists of 10mM 3,3-dimethylglutaric acid (DMGA), pH 7.0 and acetonitrile (ACN). The flow rate was 1.0mL/min with detection at λ=254nm. The method was validated for system suitability, precision, accuracy, specificity, linearity, robustness, limit of detection (LOD) and limit of quantification (LOQ), as described in ICH guidelines. The results are described as follows: (1) The system suitability includes the tailing factor, theoretical plate number and resolution, which are 0.962, 10656.11 and 9.367, respectively. (2) For specificity, the BZM and [123I]NH4I did not interfere with the retention time of the [123I]IBZM. (3) The percentage coefficient of variation for analysis of precision, including repeatability and intermediate precision, is less than 2.0%. (4) Accuracy of the method is within the range of 85-100%. (5) The range of linearity is from 100% to 70% radiochemical purity (%RCP) of [123I]IBZM, with the correlation coefficient (R) always being above 0.995. (6) The data of method robustness are within acceptance criteria. (7) The LOD and LOQ for impurity (BZM) are 0.145 and 0.50μg/mL, respectively. All of the analysis results demonstrate that this method is sensitive, specific and suitable for routine analysis of the radiochemical purity in [123I]IBZM preparations.

A new naphthol derivative, [F-18]FEONM, has been designed to be a new Tau protein PET imaging molecule for detecting Tau tangle status of Alzheimer's disease in a transgenic mouse model. In order to synthesize this molecule, 2-acetyl-6-methoxynaphthalene was the starting compound and needed five steps preparation to bonding functional and leaving group for preparing the precursor. Radiofluorination on the precursor was carried out by a modified [F-18]FDG autosynthesizer. After half an hour processing, it yielded more than 99% chemical and radiochemical purity product at up to 60% yield. Radiofluorination kinetic study showing 80% [F-18]FEONM would be produced within the first 5 min. The radiofluorination gap function factor is 0.122 for 150 min reaction. Recovery yield of crude [F-18]FEONM could be up to 60% by semi-preparative HILIC HPLC column purification with 95% ethanol elution. Brain glioma tumor mice PET imaging were performed after tail vein injecting [F-18]FEONM. Binding in mice brain tumor reached steady state after 30 min injection and shows 30–70% higher uptake compared to normal mouse. The static brain tumor uptake showed the summation accumulation binding rate was 60% faster than normal mouse. In vitro postmortem AD patient brain slice binding showed 70% higher uptake than normal brain. The uptake of spherical stem cells also showed higher association with neuronal differentiation and PET imaging of Tau and ABeta transgenic mice also showed visualized difference. The specific binding ratio of hippocampus to cerebellum of control mouse is 46.56%, cortex to cerebellum is 11.08% in a 12-month-old P301S Tau transgenic mouse; hippocampus to cerebellum is 106.66%, cortex to cerebellum is 82.48%. Relative ratio of hippocampus to cerebellum of a P301S mouse to control mouse is 2.29, cortex to cerebellum is 7.44.

Two galactose derivatives, a monovalent (99m)Tc-MAMA-MGal galactoside and a divalent (99m)Tc-MAMA-DGal galactoside, were synthesized and radiolabeled in high radiochemical purity (>98%). Dynamic microSPECT imaging and biodistribution study of two traces in normal and liver fibrosis mice showed that the (99m)Tc-MAMA-DGal revealed higher specific binding to asialoglycoprotein receptors in liver and then rapidly excreted via both hepatobiliary system and renal clearance. The results suggest that (99m)Tc-MAMA-DGal may be used as SPECT probes for noninvasive evaluation of asialoglycoprotein receptor-related liver dysfunction.

Quantification of the expression of asialoglycoprotein receptor (ASGPR), which is located on the hepatocyte membrane with high-affinity for galactose residues, can help assess ASGPR-related liver diseases. A hepatic fibrosis mouse model with lower asialoglycoprotein receptor expression was established by dimethylnitrosamine (DMN) administration. This study developed and demonstrated that 4-(18)F-fluoro-N-(6-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)hexyl)benzamide ((18)F-FBHGal), a new (18)F-labeled monovalent galactose derivative, is an asialoglycoprotein receptor (ASGPR)-specific PET probe in a normal and a hepatic fibrosis mouse models. Immunoassay exhibited a linear correlation between the accumulation of GalH-FITC, a fluorescent surrogate of FBHGal, and the amount of ASGPR. A significant reduction in HepG2 cellular uptake (P0.0001) was observed using confocal microscopy when co-incubated with 0.5μM of asialofetuin, a well known ASGPR blocking agent. Animal studies showed the accumulation of (18)F-FBHGal in fibrosis liver (14.84±1.10 %ID/g) was appreciably decreased compared with that in normal liver (20.50±1.51 %ID/g, P0.01) at 30min post-injection. The receptor indexes (liver/liver-plus-heart ratio at 30min post-injection) of hepatic fibrosis mice derived from both microPET imaging and biodistribution study were significantly lower (P0.01) than those of normal mice. The pharmacokinetic parameters (T(1/2)α, T(1/2)β, AUC and Cl) derived from microPET images revealed prolonged systemic circulation of (18)F-FBHGal in hepatic fibrosis mice compared to that in normal mice. The findings in biological characterizations suggest that (18)F-FBHGal is a feasible agent for PET imaging of hepatic fibrosis in mice and may provide new insights into ASGPR-related liver dysfunction.

Introduction 99m Tc-labeled macroaggregated albumin ( 99m Tc-MAA) scintigraphy scan is routinely performed for lung perfusion imaging and for the assessment of in vivo distribution of 90 Y-labeled SIR-Spheres prior to selective internal radiation treatment for hepatocellular carcinoma. Positron emission tomography (PET) imaging is superior to gamma scintigraphy in terms of sensitivity, spatial resolution and accuracy of quantification. This study reported that 18 F-labeled macroaggregated albumin ( 18 F-MAA) is an ideal PET imaging surrogate for 99m Tc-MAA. Methods 18 F-MAA was prepared from the commercial MAA kit via a one-step conjugation with N -succinimidyl 4- 18 F-fluorobenzoate ( 18 F-SFB). The biodistribution study and microPET/microSPECT imaging were conducted in normal SD rats after intravenous injection of 18 F-MAA/ 99m Tc-MAA. A comparison study of these two radiotracers was performed after co-injection via the intrahepatic arterial in a N1S1 hepatoma-bearing SD rat model. Results The optimal condition for 18 F-MAA preparation is coupling MAA (0.5mg) with 18 F-SFB at 45°C for 5min in a phosphate buffer of pH 8.5. 18 F-MAA was prepared in 60min with high radiochemical yield (30%–35%) and high radiochemical purity (>95%). The in vivo distribution of 18 F-MAA after intravenous injection meets the specifications of MAA depicted in European Pharmacopeia. Our study demonstrated excellent correlation between 18 F-MAA and 99m Tc-MAA in the regional distribution of tumor, liver and lungs (R 2 =0.965, 0.886 and 0.991, respectively), and also in the tumor-to-liver and tumor-to-lungs ratio (R 2 =0.965 and 0.987, respectively) in a N1S1 hepatoma-bearing SD rat model. The organ uptakes derived from animal PET/CT and SPECT/CT imaging after administration of these two tracers were in accordance with those obtained in the distribution studies. Conclusions Starting from commercial MAA kit, an efficient preparation of 18 F-MAA was successfully established. Highly correlated, almost parallel, regional distribution of 18 F-MAA and 99m Tc-MAA in both normal rats and hepatoma-bearing rats was observed. The findings, taken together, demonstrate that 18 F-MAA is an ideal surrogate for 99m Tc-MAA for clinical PET applications.

5-[(18)F]fluoro-2'-deoxyuridine ([(18)F]FUdR) was synthesized using a robotic system as a proliferation probe for PET. [(18)F]FUdR was prepared via radiofluorodestannylation reaction from its organotin precursor. Biodistribution study and microPET imaging of [(18)F]FUdR in NG4TL4 sarcoma-bearing FVB/n mice were performed. The tumor-to-blood and tumor-to-muscle ratio increased steadily from 15 (1.81 and 3.42) to 120min (9.10 and 11.9) post injection. The dynamic microPET imaging demonstrates remarkable radioactivity retention in the tumor, which is consistent with the results of biodistribution study.

A suitable three potential-time waveforms for the electrochemical detection of 2-deoxy-2-chloro-d-glucose (ClDG) by gold working electrode and palladium reference electrode have been developed and method validation was performed on Waters 2796 Bioalliance HPLC system coupled with pulsed amperometric detection (HPLC/PAD). FDG and ClDG could be completely separated by 50 mM NaOH mobile phase at a flow rate of 1.0 ml/min; 30 degrees C analytical column temperature; and E1 of 200 mV, T1 of 900 mS; E2 of -770 mV, T2 of 10 mS; E3 of 1400 mV, T3 of 10 mS; acquisition delay (AD) of 300 mS. The validation results were shown as follows: (1) in specificity study, mannose, FDG and ClDG could be completely separated and the retention times of these were 6.2, 11.1 and 13.5 min, respectively, with a total run time of 20 min; (2) the intraday repeatable precision expressed with the CV% in six successive analysis was 0.52% (for FDG) and 0.83% (for ClDG); (3) the interday variability precision expressed with the CV% value of the repeatable precision of 3 days was 0.99%, 0.52% and 0.58% for FDG and 0.71%, 0.83% and 1.24% for ClDG; both the CV% of intraday and interday reproducibilities of FDG and ClDG were better than 1.5%; (4) the accuracy and recovery of FDG and ClDG expressed with the percentage of mean value of three successive analysis were 99.75% (for FDG) and 100.68% (for ClDG) which were all greater than 95%; (5) under optimum conditions, the limit of detection of FDG and ClDG was 0.41 and 0.68 microg/ml, and the limit of quantization of FDG and ClDG was 1.24 and 2.04 microg/ml; (6) the correlation coefficient (r) value of linearity is over 0.999 by 5-50 microg/ml ranges of both compounds, respectively; (7) no interference peak effects by composition of mobile phase or increasing/decreasing flow rate or change of temperature was observed.

This study aims to assess whether emulsion of [ 125/131 I]IUdR and lipiodol (IUdR/LP) can improve delivery of IUdR into hepatoma. Methods In vitro release profile of IUdR from IUdR/LP to serum was performed. IUdR/LP was injected into N1-S1 hepatoma-bearing SD rat via hepatic artery and IUdR/normal saline (IUdR/NS) was used for comparison. Biodistribution, autoradiography, imaging and tumor DNA incorporation assay were performed. The radioactive metabolites in plasma and urine were analyzed. Radiation doses to tumor and organs were estimated. Results IUdR released from lipiodol into serum was fast. There were longer retention, more DNA incorporation and higher radiation dose of IUdR in the tumor by using IUdR/LP. IUdR/LP deposited deep in the hepatomas. Only free iodide was found in the plasma and urine after injection of IUdR/LP. Conclusions Hepatic artery injection of IUdR/LP emulsion could definitely enhance the tumor cell uptake and incorporation to DNA of *IUdR, prolong the tumor retention time and increase radiation dose to tumor. IUdR/LP may be an effective therapeutic agent for the treatment of hepatic tumors.

In vivo characterization and dosimetric analysis has been performed to evaluate the potential of pegylated liposomes as carriers of radionuclides in tumor internal radiotherapy. Methods The DTPA/PEG-liposomes were synthesized with a medium size of 110 nm, conjugated with 111 In/ 177 Lu-(oxine) 3 to afford 111 In/ 177 Lu-liposome. The stability of 111 In/ 177 Lu-liposome in serum was investigated. The biodistribution, scintigraphic imaging and pharmacokinetics of 111 In/ 177 Lu-liposomes after intravenous(i.v.) injection into C-26 tumor-bearing BALB/cByJ mice were studied. Radiation dose was estimated by MIRD-III program. Results The incorporation efficiency of 111 In/ 177 Lu into liposomes was 95%. After incubation at 37 °C for 72 h in serum, more than 83% of radioactivity was still retained in the intact 111 In/ 177 Lu-liposomes. The biodistribution of 111 In-liposomes showed that the radioactivity in the blood decreased from 23.14±8.16%ID/g at 1 h to 0.02±0.00%ID/g at 72 h post-injection (p.i.), while reaching its maximum accumulation in tumors at 48 h p.i., with half-life in blood of 10.2 h. The results were supported by that of 177 Lu-liposomes. Scintigraphic imaging with 111 In-liposomes showed unambiguous tumor images at 48 h p.i. Dose estimation showed that the absorbed dose in tumor from 177 Lu-liposomes was 5.74×10 −5 Gy/MBq. Conclusions This study provides an in vivo characterization and dosimetric evaluation for the use of liposome systems as carriers in targeted radionuclide therapy. The results suggest that adequate tumor targeting as well as dose delivered to tumors could be achieved by the use of radionuclide targeted liposomes.

We have repeated the measurement of radiogenic 82Kr and 130Xe in the mineral kitkaite, NiTeSe, and obtained half-life values of (1.2 ± 0.1) × 1020y for 82Se and (7.5 ± 0.3) × 1020y for 130Te based on the parent/daughter ratios in the kitkaite and the xenon retention age of associated uraninite. The mineralization age of the kitkaite is used to set upper limits of T1282 ⩽ 2 × 1020y and T12130 ⩽ 12.5 × 1020y.

The isotopic composition of xenon has been determined in the gas released by stepwise heating of two, geologically-old tellurium minerals — melonite, NiTe2, from the Robb-Montbray property in Quebec and altaite, PbTe, from the Mattagami Lake area of Quebec. We calculate values of 2540 ± 680 and 2550 ± 1300 for the ratio of the ββ-decay half-lives, T 1 2 128 /T 1 2 130 , from the amounts of radiogenic 128Xe and 130Xe in the melonite and the altaite, respectively, and a value of T 1 2 128 = (1.8 ± 0.7) × 10 24 y . Lepton number violation is not required by these results.