Ratio Of Radioactivity Research Articles

Development of a non-radiometric method for measuring the arterial input function of a 11C-labeled PET radiotracer

Positron emission tomography (PET) uses radiotracers to quantify important biochemical parameters in human subjects. A radiotracer arterial input function (AIF) is often essential for converting brain PET data into robust output measures. For radiotracers labeled with carbon-11 (t1/2 = 20.4 min), AIF is routinely determined with radio-HPLC of blood sampled frequently during the PET experiment. There has been no alternative to this logistically demanding method, neither for regular use nor validation. A 11C-labeled tracer is always accompanied by a large excess of non-radioactive tracer known as carrier. In principle, AIF might be obtained by measuring the molar activity (Am; ratio of radioactivity to total mass; Bq/mol) of a radiotracer dose and the time-course of carrier concentration in plasma after radiotracer injection. Here, we implement this principle in a new method for determining AIF, as shown by using [11C]PBR28 as a representative tracer. The method uses liquid chromatography-tandem mass spectrometry for measuring radiotracer Am and then the carrier in plasma sampled regularly over the course of a PET experiment. Am and AIF were determined radiometrically for comparison. The new non-radiometric method is not constrained by the short half-life of carbon-11 and is an attractive alternative to conventional AIF measurement.

Isolation, characterization and source analysis of radiocaesium micro-particles in soil sample collected from vicinity of Fukushima Dai-ichi nuclear power plant

Radioactive caesium was released during the accident of Fukushima Dai-ichi nuclear power plant (FDNPP) into the surrounding environment. In the current work, radiocaesium micro-particles (CsMPs) and radiocaesium-rich soil particles were selectively separated from soil particles as well as from each other using autoradiography-based procedure. The applied separation scheme is based on water dilution followed by drying of the soil sample prior to imaging plate autoradiography. The SEM/EDS investigation of the individual CsMPs showed that these particles have a silicate glass structure and vary in shape with a diameter less than 10 μm. For the first time, a two-stage formation mechanism was suggested for a CsMP based on shape and structure heterogeneity of its two parts. Perfect spherical core might be formed in the first stage with a remarkable lower content of Al, and relatively higher concentrations of Si and K than an outer angulated structure, which might be attached to the core sphere during a late stage.The radiocaesium-rich soil particles have bigger size than CsMPs and have a plate-like structure with cleavages inside the grains, which suggest that these particles might be a weathered biotite. The average radioactivity ratio of 134Cs/137Cs (dated March 11, 2011) in the investigated particles was found to be 1.05 ± 0.01, which confirmed that the radiocaesium in CsMPs and in the contaminated soil particles has the same source of origin, which could be unite 3 of FDNPP.

177Lu radiolabeling and preclinical theranostic study of 1C1m-Fc: an anti-TEM-1 scFv-Fc fusion protein in soft tissue sarcoma

PurposeTEM-1 (tumor endothelial marker-1) is a single-pass transmembrane cell surface glycoprotein expressed at high levels by tumor vasculature and malignant cells. We aimed to perform a preclinical investigation of a novel anti-TEM-1 scFv-Fc fusion antibody, 1C1m-Fc, which was radiolabeled with 177Lu for use in soft tissue sarcomas models.Methods1C1m-Fc was first conjugated to p-SCN-Bn-DOTA using different excess molar ratios and labeled with 177Lu. To determine radiolabeled antibody immunoreactivity, Lindmo assays were performed.The in vivo behavior of [177Lu]Lu-1C1m-Fc was characterized in mice bearing TEM-1 positive (SK-N-AS) and negative (HT-1080) tumors by biodistribution and single-photon emission SPECT/CT imaging studies. Estimated organ absorbed doses were obtained based on biodistribution results.ResultsThe DOTA conjugation and the labeling with 177Lu were successful with a radiochemical purity of up to 95%. Immunoreactivity after radiolabeling was 86% ± 4%. Biodistribution showed a specific uptake in TEM-1 positive tumor versus liver as critical non-specific healthy organ, and this specificity is correlated to the number of chelates per antibody. A 1.9-fold higher signal at 72 h was observed in SPECT/CT imaging in TEM-1 positive tumors versus control tumors.ConclusionTEM-1 is a promising target that could allow a theranostic approach to soft-tissue sarcoma, and 1C1m-Fc appears to be a suitable targeting candidate. In this study, we observed the influence of the ratio DOTA/antibody on the biodistribution. The next step will be to investigate the best conjugation to achieve an optimal tumor-to-organ radioactivity ratio and to perform therapy in murine xenograft models as a prelude to future translation in patients.

Lenticular nuclei to thalamic ratio on PET is useful for diagnosis of GLUT1 deficiency syndrome

PurposeTo establish an objective method of [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) that can assist in the diagnosis of glucose transporter 1 deficiency syndrome (GLUT1-DS). MethodsFDG-PET was performed in 8 patients with a mean age of 12.5 years (range, 2–22 years) with GLUT1-DS. Their PET findings were compared with those of 45 controls with a mean age of 11.2 years (range, 2–21 years) by statistical parametric mapping (SPM12, Welcome Neurological Institute). The controls had epilepsy of unknown etiology and normal MRI findings. The age-adjusted ratios of mean radioactivities in regions of interest (ROIs) of bilateral lenticular nuclei, thalami, and the whole cerebral cortex were also measured. The sensitivities and specificities of the ratios for the differential diagnosis of GLUT1-DS were also determined. ResultsSPM showed significantly decreased uptake in bilateral thalami and increased uptake in bilateral lenticular nuclei in patients with GLUT1-DS. There were no areas in the cerebral cortex with significant differences between patients and controls. On ROI analysis, by setting the cut-off value of the age-adjusted lenticular nuclei/thalami radioactivity ratio to 1.54, patients with GLUT1-DS were differentiated from controls with sensitivity of 1.00 and specificity of 0.98. ConclusionThe age-adjusted lenticular nuclei/thalami radioactivity ratio on PET can distinguish patients with GLUT1-DS from patients with epilepsy of unknown etiology with high sensitivity and specificity. It is important to pay attention to the metabolism of the lenticular nuclei and thalami on PET for the diagnosis of GLUT1-DS.

Dual-Phase 99mTc-MIBI SPECT/CT in the Characterization of Enhancing Solid Renal Tumors: A Single-Institution Study of 147 Cases.

The aim of this study was to investigate the value of dual-phase Tc-MIBI SPECT/CT in the differential diagnosis between benign and malignant enhancing solid renal tumors. Totally, 180 patients were imaged with dual-phase Tc-MIBI SPECT/CT, which was performed 30 minutes and 90 minutes after Tc-MIBI administration. Among them, 147 patients with 148 histologically proved solid renal tumors met the selection criteria and were included for the final analysis. Relative quantification was performed by measuring the radioactive uptake ratio of tumor to the normal renal parenchymal background for both early and delayed images. Benign renal tumors (4 renal oncocytomas and 8 lipid-poor angiomyolipomas) demonstrated a significantly higher early relative uptake value (ERUV) and delayed relative uptake value (DRUV) than malignant renal tumors (n = 136; both P < 0.0001). The ERUV cutoff value of 0.53 helped to differentiate benign from malignant renal tumors, with sensitivity of 100%, specificity of 94.8%, and accuracy of 95.3% for the diagnosis of benign renal tumors. The DRUV cutoff value of 0.50 helped to differentiate benign from malignant renal tumors, with sensitivity of 100%, specificity of 96.3%, and accuracy of 96.6% for the diagnosis of benign renal tumors. There was no statistically significant difference between the efficacy of ERUV and DRUV in the differential diagnosis between benign and malignant renal tumors (P = 0.5). The efficacies of ERUV and DRUV were all significantly higher than the retention index (both P < 0.0001). Both early and delayed phase Tc-MIBI SPECT/CT are helpful for distinguishing benign renal oncocytoma and lipid-poor angiomyolipoma from malignant renal tumors, and the delayed phase imaging tends to show higher diagnostic accuracy.

Vertical distribution of radionuclides in Lake Qinghai, Qinghai-Tibet Plateau, and its environmental implications

Radionuclides are widely used to perform geochronologic investigations of the trace sediment deposition process in aquatic environments on different temporal scales. This study presents the activities of radionuclides to select a reasonable geochronologic dating method and study the sediment depositional environment in Lake Qinghai on the Qinghai-Tibet Plateau. The range of activities (Bq.kg−1) of 137Cs, 226Ra, 238U, 228Ra, 228Th, and 40K were 2–103, 24–49, 33–156, 20–49, 30–50, and 403–664, respectively. The sedimentation flux was calculated as 1.66 × 106 ton.a−1 based on the summary sedimentation rate in Lake Qinghai, and the sediment contributions from rivers, authigenic carbonates, lacustrine organisms, and atmospheric deposition were 45.18%, 22.44%, 3.02%, and 29.36%, respectively. The decreased 226Ra/238U radioactivity ratios from the catchment to the lake centre indicated that the removal of uranium relative to its daughter products occurs during erosion processes. The positive 228Thex (excess 228Th) values in the upper 1 cm of the sediment suggested that the sediment in the top 1 cm have been resuspended, mixed and/or transported. The distribution of 137Cs in the sediments indicated that the maximum activity of 137Cs in the sediments corresponds to the 1963 peak in the global fallout from atmospheric nuclear weapons testing; moreover, the 1986 Chernobyl accident signal was difficult to identify. The use of 137Cs as a chronologic tool must be performed carefully due to its migration process in sediments.

214Bi/214Pb radioactivity ratio three-year monitoring in rainwater in Prague

Abstract Continuous monitoring of natural gamma radiation in air has been carried out, during December 2014 – January 2018, with 1-min cyclic measurement in Prague, Czech Republic using a NaI(Tl) probe. The 214Bi/214Pb ratio as a tracer in rainwater has been investigated to study its variations related to both the ambient dose equivalent rate per hour and the amount of rainfall. A hybrid methodology for time series analysis, composed of the aggregation of two signal decomposition methods (multiple linear regression and empirical mode decomposition) and one forecasting method (support vector regression), has been applied to identify the anomalies in the studied signals in order to better find correlations among them. The results show a strong correlation between the ambient dose equivalent rate and the 214Bi/214Pb ratio values and between both these signals and rainfall amount ≥5 mm/h. Furthermore, the considered descendants of radon are mainly responsible for the overall ambient dose equivalent rate.

Synthesis and evaluation of novel radioiodinated anthranilate derivatives for in vivo imaging of vascular endothelial growth factor receptor with single-photon emission computed tomography.

Angiogenesis facilitates tumor survival and promotes malignancy. The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) tyrosine kinase (TK) signaling pathway is a key factor mediating angiogenesis, suggesting that this pathway may be a target for diagnosis and therapy. In this study, we aimed to develop small molecule radioiodinated probes applicable for in vivo VEGFR imaging considering the versatility and usefulness of single-photon emission computed tomography (SPECT). We designed and synthesized four radioiodinated anthranilate compounds (6a-d) based on the structure of an anticancer drug targeting VEGFR-TK. The inhibitory potencies of corresponding cold compounds 4a-d and in vitro stability of compounds 6a-d were assessed by cellular proliferation inhibition assays and radio thin-layer chromatography after incubation in neutral solution. In vivo biodistributions were evaluated by determining radioactivity in tissues of interest after intravenous injection of test compounds in tumor-bearing mice. In vitro and in vivo blocking experiments using a selective VEGFR-TK inhibitor and SPECT/computed tomography (CT) imaging were performed in tumor-bearing mice. The radioiodinated compounds 6a-d were obtained with more than 68.0% radiochemical yield and more than 95% radiochemical purity. Because compounds 4a-d showed high inhibitory potencies and compounds 6c and 6d showed high in vitro stability, 6c ([125I]m-NPAM) and 6d ([125I]p-NPAM) were further evaluated. Analysis of the in vivo biodistribution revealed a tumor to blood radioactivity ratio of greater than 4 at 24h after [125I]p-NPAM administration. Accumulation of radioactivity in cultured tumor cells and tumor xenografts after [125I]p-NPAM administration was significantly blocked by inhibitor pretreatment. Tumors were clearly imaged at 24h after [125I]p-NPAM injection with SPECT/CT in comparison to that in inhibitor-pretreated tumor-bearing mice. [125I]p-NPAM may have potential applications as a lead compound for future development of a clinically usable VEGFR imaging probe for SPECT.

Analysis of whole-body bone scintigraphy and SPECT/CT imaging in osteoid osteoma

Objective To analyze features of osteoid osteoma on whole-body bone scan (WBS) and SPECT/CT imaging. Methods From January 2010 to December 2018, 70 patients (50 males, 20 females, age: 4-66 years) with osteoid osteoma confirmed by pathology were enrolled from the Affiliated Hospital of Southwest Medical University. All patients underwent WBS and SPECT/CT imaging and imaging features were retrospectively analyzed. Results A total of 70 lesions were found by WBS combined with SPECT/CT imaging, and 26 lesions (37.1%, 26/70) were found in the femur and 25 lesions (35.7%, 25/70) in the tibia. The radioactive ratio of target lesion to non-target lesion (T/NT) was 3.7±1.2 in 56 patients who underwent three-phase bone imaging. WBS showed that 48 lesions (68.6%, 48/70) were round (or nearly round), 21 lesions (30%, 21/70) were spindle-shaped, and 1 lesion (1.4%, 1/70) was irregular-shaped, while SPECT/CT imaging showed that 69 lesions (98.6%, 69/70) were round (or round) and 1 lesion (1.4%, 1/70) was irregular-shaped. The double-density sign was found in 48 lesions (68.6%, 48/70) by WBS and in 59 lesions (84.3%, 59/70) by SPECT/CT imaging. SPECT/CT imaging detected nidus in 59 lesions (84.3%, 59/70) and calcification or ossification ( target sign ) in 27 lesions (38.6%, 27/70). Conclusion The typical features of osteoid osteoma on WBS and SPECT/CT imaging include double density sign , nidus and target sign , which contribute to the diagnosis of osteoid osteoma. Key words: Osteoma, osteoid; Radionuclide imaging; Tomography, emission-computed, single-photon; Tomography, X-ray computed; Technetium Tc 99m medronate

Pretreatment conditions for detecting &lt;sup&gt;134&lt;/sup&gt;Cs -Eight years after the Fukushima Daiichi nuclear accident-

134Cs is an activation product with a short half-life (2.06 years) that was released during the Fukushima Daiichi nuclear disaster. It is an important indicator of contamination from the disaster because it has been more than 30 years since the last event when 134Cs was released. The radioactivity ratio of 137Cs to 134Cs was approximately 1 at the time of the accident, and thus, it is possible to quantitatively evaluate the sources of 137Cs from the radioactivity of 134Cs in environmental samples. In particular, because the radioactivity of 134Cs in foodstuffs in Japan is low due to its short half-life, pretreatment (concentration) is essential for quantification. For analyses using a 2-L Marinelli vessel and a conventional HPGe semiconductor detector (relative efficiency 25%), the detection limit for 134Cs was approximately 0.05 Bq/kg without pretreatment. For the 137Cs contamination source segregation in Japan in March 2020, the radioactivity in samples must be at least 0.83 Bq/kg of 137Cs. This study provided guideline requirements for sample volume and pretreatment.

Reduction of the fluorine-18-labeled fluorodeoxyglucose dose for clinically dedicated breast positron emission tomography

PurposeTo determine the clinically acceptable level of reduction in the injected fluorine-18 (18F)-labeled fluorodeoxyglucose (18F-FDG) dose in dedicated breast positron emission tomography (dbPET).MethodsA breast phantom with four spheres exhibiting various diameters (5, 7.5, 10, and 16 mm), a background 18F-FDG radioactivity of 2.28 kBq/mL, and a sphere-to-background radioactivity ratio of 8:1 was used. True dose-reduced dbPET images were obtained by data acquisition for 20 min in list mode at multiple time points over 7 h of radioactive decay. Simulated dose-reduced images were generated by reconstruction with a portion of the list mode acquisition data. True and simulated dose-reduced images were visually and quantitatively compared. On the basis of the phantom study, dbPET images for 32 breasts of 28 women with abnormal uptake were generated after simulated reduction of the injected 18F-FDG doses; these images were compared with those acquired using current clinical doses.ResultsThere were no qualitative differences between true and simulated dose-reduced phantom images. The phantom study revealed that the minimal required dose was 12.5% for the detection of 5-mm spheres and 25% for precise semi-quantification of FDG in the spheres. The 7-min reconstruction with a 100% dose was defined as the reference for the clinical study. The image quality and lesion conspicuity were clinically acceptable for the 25% dose images. Lesion detectability on the 12.5% dose images was maintained despite image quality degradation.ConclusionsIn summary, 25% of the standard 18F-FDG dose for dbPET can provide a clinically acceptable image quality, while 12.5% of the standard dose results in acceptable quality in terms of lesion detection when lesions are located at a sufficient distance from the edge of the dbPET detector.

Evaluating Changes of Tumor Hypoxia Using 99Tcm-MNLS Hypoxic Imaging

Background: Hypoxia is an important cause of recurrence and metastasis of malignant tumors. Noninvasive detection of the extent of hypoxic areas of tumors is essential for delineation of radiotherapy target areas and dose. Objectives: To investigate the feasibility of 99Tcm-2-(2-methyl-5-nitro-1H-imidazol-1-yl) ethyl dihydrogen phosphate (99Tcm-MNLS) hypoxic imaging to monitor the tumor hypoxic state in tumor-bearing mice after radiotherapy. Materials and Methods: Tumor-bearing mice were divided into eight groups: imaged 24 hours before radiotherapy (A24 h before), imaged immediately after radiotherapy (Aimmediately), imaged 24 hours after radiotherapy (A24 h), imaged 48 hours after radiotherapy (A48 h), and the corresponding control groups. Mice in each group received hypoxia imaging at the corresponding time point to calculate the radioactivity ratio of tumor/non-tumor (T/NT). Hypoxia inducible factor-1α (HIF-1α) was determined by immunohistochemistry to investigate the relationship between T/NT ratio and HIF-1α expression in radiotherapy and control groups. Results: T/NT ratio and the expression of HIF-1α in A24 h group were not significantly different from those in A24 h before and control groups, but lower than those in the Aimmediately group and higher than those in the A48 h group. T/NT ratio and the expression of HIF-1α in the A24 h before group had no significant difference compared with those in its control group, while those in the Aimmediately group were remarkably higher than those in its control group. On the other hand, those in A48 h group were lower than those in its control group. There was a positive correlation between T/NT ratio and HIF-1α expression in radiotherapy group and control group at different time points. Conclusion: 99Tcm-MNLS tumor hypoxic imaging can evaluate the tumor hypoxic status of tumor-bearing mice after radiotherapy.

Preparation and imaging of 18F-VUIIS1008 targeting TSPO in rheumatoid arthritis model

Objective To synthesize a novel 18F labeled probe targeting translocator protein (TSPO) ligand 2-(5, 7-diethyl-2-(4-(2-fluoroethoxy)phenyl)pyrazolo[1, 5-a]pyrimidin-3-yl)-N, N-diethylacetamide (VUIIS1008), and evaluate its biodistribution and imaging in rheumatoid arthritis (RA) model. Methods The tosylate substrate was labeled with 18F using a tosyloxy for fluorine nucleophilic aliphatic substitution to obtain 18F-VUIIS1008. The labeling efficiency, radiochemical purity, and stability in vitro were determined. In vitro cellular uptake and competitive binding assay were performed on RAW264.7 macrophage cells. Biodistribution and microPET/CT imaging were investigated on RA mice established by Complete Freund′s Adjuvant. Two-sample t test was used to analyze the data. Results 18F-VUIIS1008 was synthesized with the labeling yield up to (41.00±5.00)%, the radiochemical purity >98.00%, and the specific radioactivity >1.52×108 MBq/mmol. 18F-VUIIS1008 was highly stable with the radiochemical purity >98.00% at 4 h after incubation in mouse serum. In vitro, it also exhibited high specific TSPO binding in RAW264.7 macrophage cells. The uptake ratio was (14.00±0.30)% at 1 h after incubation, and decreased significantly ((4.00±0.70)%; t=12.894, P<0.05) after adding excessive unlabeled VUIIS1008. The half maximal inhibitory concentration (IC50) of 18F-VUIIS1008 binding to TSPO was 0.05 nmol/L in RAW264.7 macrophage cells. In vivo distribution results showed that the uptake of 18F-VUIIS1008 in the left arthritic ankles reached the peak value of (1.33±0.02) percentage activity of injection dose per gram of tissue (%ID/g) at 1 h after injection. The radioactivity ratio of left ankle arthritic tissue to blood (A/B) and to normal muscle (A/M) was 4.40±0.22 and 1.65±0.07 respectively. MicroPET/CT imaging demonstrated that 18F-VUIIS1008 could specifically target and retained in the inflammation site. Conclusion 18F-VUIIS1008 can be easily synthesized with high radiochemical purity and can clearly visualized in RA imaging with low background, suggesting its potential as a novel promising molecular probe targeting TSPO for RA PET imaging. Key words: Membrane transport proteins; Pyrazoles; Pyrimidines; Fluorine radioisotopes; Arthritis, rheumatoid; Positron-emission tomography; Tomography, X-ray computed; Mice

Temporal Variation of Radionuclide Contamination of Marine Plants on the Fukushima Coast after the East Japan Nuclear Disaster.

As a result of the Great East Japan Earthquake and associated tsunami in March 2011, the Fukushima Daiichi Nuclear Power Plant (FDNPP) released a large amount of radioactive material into the environment, resulting in contamination of many marine organisms. In this study, 15 marine algal species and a seagrass species were collected from the sublittoral zone of the Iwaki Coast of Fukushima Prefecture from May 2012 to June 2015 and analyzed for variations in 110mAg, 134Cs, and 137Cs over time. The results indicated that (1) 110mAg, 134Cs, and 137Cs were present in all marine plants collected in May 2012, (2) the concentration of 110mAg in the seagrass Phyllospadix iwatensis decreased significantly over time while the ecological half-life of 110mAg in P. iwatensis was longer at locations closer to the FDNPP, and (3) the 110mAg/137Cs radioactivity ratio of P. iwatensis was remarkably high until 2015, indicating that detectable 110mAg was present in the coastal environment 4 years after the accident. The concentration of 110mAg in P. iwatensis was higher than those in other marine algae, demonstrating a species-specific mechanism of accumulation.

Synthesis and characterization of novel radiofluorinated probes for positron emission tomography imaging of monoamine oxidase B.

Monoamine oxidase B (MAO-B), predominantly expressed in glial cells, plays an important role in neurotransmitter regulation, and MAO-B activity relates to several neuronal diseases. Here, we aimed to develop a radiofluorinated MAO-B imaging probe based on the structure of a selective MAO-B inhibitor, MD-230254. We synthesized and evaluated a series of compounds in vitro and in vivo. A series of fluorinated analogs of MD-230254 were synthesized and evaluated for inhibitory potency and selectivity toward MAO-B. 5-[4-(2-[18 F]Fluorobenzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-2(3H)-one (2-[18 F]FBPO) was synthesized from a corresponding tributylstannyl precursor and [18 F]CH3 COOF. Biodistribution after intravenous injection of 2-[18 F]FBPO was evaluated in male ddY mice with or without pretreatment by inhibitors. Among the compounds synthesized and evaluated, 2-FBPO showed high inhibitory potency and selectivity toward MAO-B comparable with MD-230254. 2-[18 F]FBPO was successfully synthesized by an electrophilic reaction with a high radiochemical purity of more than 99%. 2-[18 F]FBPO was efficiently taken up by the brain and showed rapid blood clearance, which provided a brain/blood radioactivity ratio of 3.7 at 90 minutes postinjection. The brain radioactivity was significantly decreased by pretreatment with an MAO-B selective inhibitor. The great potential of 2-[18 F]FBPO as an MAO-B imaging probe, applicable to a variety of diseases, is indicated.

Evaluation of absorption, distribution, metabolism, and excretion of [14C]-rucaparib, a poly(ADP-ribose) polymerase inhibitor, in patients with advanced solid tumors

SummaryRucaparib, a poly(ADP-ribose) polymerase inhibitor, is licensed for use in recurrent ovarian, fallopian tube, or primary peritoneal cancer. We characterized the absorption, distribution, metabolism, and elimination of rucaparib in 6 patients with advanced solid tumors following a single oral dose of [14C]-rucaparib 600 mg (≈140 μCi). Total radioactivity (TRA) in blood, plasma, urine, and feces was measured using liquid scintillation counting. Unchanged rucaparib concentrations in plasma were determined using validated liquid chromatography with tandem mass spectrometry. Maximum concentration (Cmax) of TRA and unchanged rucaparib in plasma was 880 ng Eq/mL and 428 ng/mL, respectively, at approximately 4 h post dose; terminal half-life was >25 h for both TRA and rucaparib. The plasma TRA-time profile was parallel to yet higher than that of rucaparib, suggesting the presence of metabolites in plasma. Mean blood:plasma ratio of radioactivity was 1.0 for Cmax and 0.8 for area under the concentration-time curve from time zero to infinity. Mean postdose recovery of TRA was 89.3% over 12 days (71.9% in feces; 17.4% in urine). Unchanged rucaparib and M324 (oxidative metabolite) were the major components in plasma, contributing to 64.0% and 18.6% of plasma radioactivity, respectively. Rucaparib and M324 were the major rucaparib-related components (each ≈7.6% of dose) in urine, whereas rucaparib was the predominant component (63.9% of dose) in feces. The high fecal recovery of unchanged rucaparib could be attributed to hepatic excretion and/or incomplete oral absorption. Overall, these data suggest that rucaparib is eliminated through multiple pathways, including metabolism and renal and biliary excretion.

Gallium-68-Labelled Indocyanine Green as a Potential Liver Reserve Imaging Agent

Objective This work evaluated the potential of 68Ga-labelledNOTA-ICG (1,4,7-triazacyclononane-1,4,7-triacetic acid indocyanine green) for liver reserve imaging. Methods To determine the optimal conditions for generating 68Ga-NOTA-ICG, various reaction parameters were implemented. Quality control analysis was performed using different chromatography techniques. The in vitro and in vivo stability was also measured at specific time points. The radioactivity ratio between n-octanol and water was determined to evaluate the water solubility of 68Ga-NOTA-ICG. The plasma-protein binding rate of the labelled compound was determined by the methanol method. The biodistribution and imaging findings were evaluated in normal animals at different time points after injection. A preliminary imaging evaluation was performed using an animal model of hepatic ischaemia-reperfusion injury, which was confirmed by pathology. Results 68Ga-NOTA-ICG was prepared with very high radiochemical purity (>98%) by reacting at 90°C for 10 min at pH = 3.5∼4.0, with excellent stability in vivo and in vitro (>95% 3 h postpreparation). The in vitro plasma-protein binding rate of 68Ga-NOTA-ICG was 13.01 ± 0.7%, and it showed strong water solubility (log P=−2.01 ± 0.04). We found that in addition to excretion through the biliary tract and intestines, 68Ga-NOTA-ICG can be excreted through the urinary tract. The image quality of 68Ga-NOTA-ICG was very high; imaging agent retained in the area of liver injury could clearly be observed. Conclusion This is the first report on a 68Ga-labelled NOTA-ICG fragment for liver reserve function studies. This complex has promise as a candidate agent for liver reserve imaging.

Tau Positron-Emission Tomography in Former National Football League Players

BackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been associated with a history of repetitive head impacts. The neuropathological diagnosis is based on a specific pattern of tau deposition with minimal amyloid-beta deposition that differs from other disorders, including Alzheimer’s disease. The feasibility of detecting tau and amyloid deposition in the brains of living persons at risk for CTE has not been well studied.MethodsWe used flortaucipir positron-emission tomography (PET) and florbetapir PET to measure deposition of tau and amyloid-beta, respectively, in the brains of former National Football League (NFL) players with cognitive and neuropsychiatric symptoms and in asymptomatic men with no history of traumatic brain injury. Automated image-analysis algorithms were used to compare the regional tau standardized uptake value ratio (SUVR, the ratio of radioactivity in a cerebral region to that in the cerebellum as a reference) between the two groups and to explore the associations of SUVR with symptom severity and with years of football play in the former-player group.ResultsA total of 26 former players and 31 controls were included in the analysis. The mean flortaucipir SUVR was higher among former players than among controls in three regions of the brain: bilateral superior frontal (1.09 vs. 0.98; adjusted mean difference, 0.13; 95% confidence interval [CI], 0.06 to 0.20; P<0.001), bilateral medial temporal (1.23 vs. 1.12; adjusted mean difference, 0.13; 95% CI, 0.05 to 0.21; P<0.001), and left parietal (1.12 vs. 1.01; adjusted mean difference, 0.12; 95% CI, 0.05 to 0.20; P=0.002). In exploratory analyses, the correlation coefficients in these three regions between the SUVRs and years of play were 0.58 (95% CI, 0.25 to 0.79), 0.45 (95% CI, 0.07 to 0.71), and 0.50 (95% CI, 0.14 to 0.74), respectively. There was no association between tau deposition and scores on cognitive and neuropsychiatric tests. Only one former player had levels of amyloid-beta deposition similar to those in persons with Alzheimer’s disease.ConclusionsA group of living former NFL players with cognitive and neuropsychiatric symptoms had higher tau levels measured by PET than controls in brain regions that are affected by CTE and did not have elevated amyloid-beta levels. Further studies are needed to determine whether elevated CTE-associated tau can be detected in individual persons. (Funded by Avid Radiopharmaceuticals and others.)

Clinical features and therapeutic outcomes of patients with papillary thyroid microcarcinomas and larger tumors.

The aim of this study was to identify clinical features and therapeutic outcomes of patients with papillary thyroid cancer (PTC) according to tumor diameter and evaluate the correlation of neck lymph node (LN) involvement of papillary thyroid microcarcinoma (PTMC) according to patients' age. We divided 467 patients into two groups according to tumor diameter: PTMC group (≤1 cm) and non-PTMC group (>1 cm). The clinical data were analyzed retrospectively. Thereafter, we divided the PTMC patients into three subgroups according to age: young subgroup (<45 years), middle subgroup (45-54 years), and old subgroup (≥55 years). A further study about clinical features, especially the neck LN involvement in three subgroups, was analyzed. All patients received radioiodine ablation at least once. There were more patients with a single cancer lesion and cancer in the unilateral lobe, less number of neck LN involvement, fewer patients with neck lymph node metastasis (LNM), and more patients with Hashimoto's thyroiditis in PTMC group than in non-PTMC group. At the further evaluation, 58.03% patients maintained clinical remission, which was more in the PTMC group than in non-PTMC group. There was no significant difference in recurrence, but the disease-free survival rate of patients in the PTMC group was higher than in the non-PTMC group. In the PTMC group, the radioactive iodine curative ratio in younger patients is lower than that in the other two subgroups. Both the LNM and central LNM (CLNM) rates were significantly higher in young patients compared with older patients. In addition, the LNM-positive group had more male patients, larger tumor size, and higher thyroglobulin antibody level. Both LNM and the CLNM rates were significantly higher in the young subgroup than in the older subgroup. Young and middle age and extrathyroid extension were independent risk factors for neck LNM. Unlike LNM, young age, extrathyroid extension, and male sex were independent risk factors for CLNM. Some PTMCs were less aggressive and the therapeutic outcomes of them were better than non-PTMC. Moreover, PTMCs in young patients were more aggressive, especially in LNM. Hence, clinicians should consider an individualized treatment according to tumor characteristics and age to achieve better therapeutic efficacy.

Development of a p38α-selective radioactive probe for qualitative diagnosis of cancer using SPECT.

p38 mitogen-activated protein (MAP) kinase (p38α) has drawn attention as a new target molecule for the treatment and diagnosis of cancer, and its overexpression and activation have been reported in various types of cancer. In this study, a single photon emission computed tomography (SPECT) imaging probe of p38α was developed to noninvasively image p38α activity for effective qualitative diagnosis of cancer. Pyrrolepyridine derivatives, m-YTM and p-YTM, were designed and synthesized based on the structure of the p38α-selective inhibitor. Radioactive iodine-labeled m-YTM, [125I]m-YTM, was synthesized because m-YTM greatly inhibited the phosphorylation of p38α upon examining the inhibitory effects of the compounds. After investigating the binding affinity of [125I]m-YTM to the recombinant p38α, a saturation binding experiment using activated p38α and inactive p38α was performed to determine the binding site. Uptake of [125I]m-YTM into various cancer cell lines was investigated, and the pharmacokinetics was evaluated using tumor-bearing mice. The inhibitory activity of m-YTM was approximately 13 times higher than that of SB203580, a p38α-selective inhibitor. The binding site of [125I]m-YTM was estimated to be the p38α activating site, similar to that of SB203580, because the [125I]m-YTM bound strongly to both activated p38α and inactive p38α. Various different cancer cells incorporated [125I]m-YTM; however, its accumulation was significantly reduced by treatment with SB203580. Pharmacokinetics study of [125I]m-YTM in B-16 tumor-bearing mice was examined which revealed high accumulation of radioactivity in tumor tissues. The ratios of radioactivity in the B-16 tumor to that in blood were 3.1 and 50 after 1 and 24h, respectively. The ratio of radioactivity in the tumor to that in blood in the tumor-bearing mice generated using other cancer cell lines was also ≥ 1 at 1h after the administration of the probe. This study suggests that [123I]m-YTM has potential as a p38α imaging probe effective for various cancer types.