Differential uptake of (68)Ga-DOTATOC and (68)Ga-DOTATATE in PET/CT of gastroenteropancreatic neuroendocrine tumors

PURPOSE Abundant expression of somatostatin receptors (sst) is a characteristic of neuroendocrine tumors (NET). Thus, radiolabeled somatostatin analogs have emerged as important tools for both in vivo diagnosis and therapy of NET. The two compounds most often used in functional imaging with positron emission tomography (PET) are (68)Ga-DOTATATE and (68)Ga-DOTATOC. Both analogs share a quite similar sst binding profile. However, the in vitro affinity of (68)Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately tenfold higher than that of (68)Ga-DOTATOC. This difference may affect their efficiency in detection of NET lesions, as sst2 is the predominant receptor subtype on gastroenteropancreatic NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs ((68)Ga-DOTATATE and (68)Ga-DOTATOC) in the same patients with gastroenteropancreatic NET. PATIENTS AND METHODS Twenty-seven patients with metastatic gastroenteropancreatic NET underwent (68)Ga-DOTATOC and (68)Ga-DOTATATE PET/CT as part of the workup before prospective peptide receptor radionuclide therapy (PRRT). The performance of both imaging methods was analyzed and compared for detection of individual lesions per patient and for eight defined body regions. A region was regarded as positive if at least one lesion was detected in that region. In addition, radiopeptide uptake in terms of the maximal standardized uptake value (SUV(max)) was compared for concordant lesions and renal parenchyma. RESULTS Fifty-one regions were found positive with both (68)Ga-DOTATATE and (68)Ga-DOTATOC. Overall, however, significantly fewer lesions were detected with (68)Ga-DOTATATE in comparison with (68)Ga-DOTATOC (174 versus 179, p < 0.05). Mean (68)Ga-DOTATATE SUV(max) across all lesions was significantly lower compared with (68)Ga-DOTATOC (16.9 ± 6.8 versus 22.1 ± 12.0, p < 0.01). Mean SUV(max) for renal parenchyma was not significantly different between (68)Ga-DOTATATE and (68)Ga-DOTATOC (12.6 ± 2.6 versus 12.6 ± 2.7). CONCLUSIONS (68)Ga-DOTATOC and (68)Ga-DOTATATE possess similar diagnostic accuracy for detection of gastroenteropancreatic NET lesions (with a potential advantage of (68)Ga-DOTATOC) despite their evident difference in affinity for sst2. Quite unexpectedly, maximal uptake of (68)Ga-DOTATOC tended to be higher than its (68)Ga-DOTATATE counterpart. However, tumor uptake shows high inter- and intraindividual variance with unpredictable preference of one radiopeptide. Thus, our data encourage the application of different sst ligands to enable personalized imaging and therapy of gastroenteropancreatic NET with optimal targeting of tumor receptors.

Thermal neutron capture effects in radioactive and stable nuclide systems

Neutron capture effects in meteorites and lunar surface samples have been successfully used in the past to study exposure histories and shielding conditions. In recent years, however, it turned out that neutron capture effects produce a nuisance for some of the short-lived radionuclide systems. The most prominent example is the 182Hf-182W system in iron meteorites, for which neutron capture effects lower the 182W/184W ratio, thereby producing too old apparent ages. Here, we present a thorough study of neutron capture effects in iron meteorites, ordinary chondrites, and carbonaceous chondrites, whereas the focus is on iron meteorites. We study in detail the effects responsible for neutron production, neutron transport, and neutron slowing down and find that neutron capture in all studied meteorite types is not, as usually expected, exclusively via thermal neutrons. In contrast, most of the neutron capture in iron meteorites is in the epithermal energy range and there is a significant contribution from epithermal neutron capture even in stony meteorites. Using sophisticated particle spectra and evaluated cross section data files for neutron capture reactions we calculate the neutron capture effects for Sm, Gd, Cd, Pd, Pt, and Os isotopes, which all can serve as neutron-dose proxies, either in stony or in iron meteorites. In addition, we model neutron capture effects in W and Ag isotopes. For W isotopes, the GCR-induced shifts perfectly correlate with Os and Pt isotope shifts, which therefore can be used as neutron-dose proxies and permit a reliable correction. We also found that GCR-induced effects for the 107Pd-107Ag system can be significant and need to be corrected, a result that is in contrast to earlier studies.

The Galactic Cosmic Ray Intensity over the Past 106–109 Years as Recorded by Cosmogenic Nuclides in Meteorites and Terrestrial Samples

Concentrations of stable and radioactive nuclides produced by cosmic ray particles in meteorites allow us to track the long term average of the primary flux of galactic cosmic rays (GCR). During the past ∼10 Ma, the average GCR flux remained constant over timescales of hundreds of thousands to millions of years, and, if corrected for known variations in solar modulation, also during the past several years to hundreds of years. Because the cosmic ray concentrations in meteorites represent integral signals, it is difficult to assess the limits of uncertainty of this statement, but they are larger than the often quoted analytical and model uncertainties of some 30%. Time series of concentrations of the radionuclide 10Be in terrestrial samples strengthen the conclusions drawn from meteorite studies, indicating that the GCR intensity on a ∼0.5 million year scale has remained constant within some ±10% during the past ∼10 million years. The very long-lived radioactive nuclide 40K allows to assess the GCR flux over about the past one billion years. The flux over the past few million years has been the same as the longer-term average in the past 0.5–1 billion years within a factor of ∼1.5. However, newer data do not confirm a long-held belief that the flux in the past few million years has been higher by some 30–50% than the very long term average. Neither does our analysis confirm a hypothesis that the iron meteorite data indicate a ∼150 million year periodicity in the cosmic ray flux, possibly related to variations in the long-term terrestrial climate.

NOVEL AMINO ACID TRANSPORTER-TARGETED RADIOTRACERS FOR BREAST CANCER IMAGING

Breast cancer is the most common malignancy among women in the world. Its 5-year survival rate ranges from 23.4% in patients with stage IV to 98% in stage I disease, highlighting the importance of early detection and diagnosis. 18F-2-Fluoro-2-deoxy-glucose (18F-FDG), using positron emission tomography (PET), is the most common functional imaging tool for breast cancer diagnosis currently. Unfortunately, 18F-FDG-PET has several limitations such as poorly differentiating tumor tissues from inflammatory and normal brain tissues. Therefore, 18F-labeled amino acid-based radiotracers have been reported as an alternative, which is based on the fact that tumor cells uptake and consume more amino acids to sustain their uncontrolled growth. Among those radiotracers, 18F-labeled tyrosine and its derivatives have shown high tumor uptake and great ability to differentiate tumor tissue from inflammatory sites in brain tumors and squamous cell carcinoma. They enter the tumor cells via L-type amino acid transporters (LAT), which were reported to be highly expressed in many cancer cell lines and correlate positively with tumor growth. Nevertheless, the low radiosynthesis yield and demand of an on-site cyclotron limit the use of 18F-labeled tyrosine analogues. In this study, four Technetium-99m (99mTc) labeled tyrosine/ AMT (α-methyl tyrosine)-based radiotracers were successfully synthesized and evaluated for their potentials in breast cancer imaging. In order to radiolabel tyrosine and AMT, the chelators N,N’-ethylene-di-L-cysteine (EC) and 1,4,8,11-tetra-azacyclotetradecane (N4 cyclam) were selected to coordinate 99mTc. These chelators have been reported to provide stable chelation ability with 99mTc. By using the chelator technology, the same target ligand could be labeled with different radioisotopes for various imaging modalities for tumor diagnosis, or for internal radionuclide therapy in future. Based on the in vitro and in vivo evaluation using the rat mammary tumor models, 99mTc-EC-AMT is considered as the most suitable radiotracer for breast cancer imaging overall, however, 99mTc-EC-Tyrosine will be more preferred for differential diagnosis of tumor from inflammation.

Atmospheric Soluble Dust Records from a Tibetan Ice Core: Possible Climate Proxies and Teleconnection With the Pacific Decadal Oscillation

In autumn 2005, a joint expedition between the University of Maine and the Institute of Tibetan Plateau Research recovered three ice cores from Guoqu Glacier (33 degrees 34'37.80 '' N, 91 degrees 10'35.3 '' E, 5720 m above sea level) on the northern side of Mt. Geladaindong, central Tibetan Plateau. Isotopes ( delta(18)O), major soluble ions (Na(+), K(+), Mg(2+), Ca(2+), Cl(-), NO(3)(-), SO(4)(2-)), and radionuclide (beta-activity) measurements from one of the cores revealed a 70-year record (1935-2005). Statistical analysis of major ion time series suggests that atmospheric soluble dust species dominate the chemical signature and that background dust levels conceal marine ion species deposition. The soluble dust time series have interspecies relations and common structure (empirical orthogonal function (EOF) 1), suggesting a similar soluble dust source or transport route. Annual and seasonal correlations between the EOF 1 time series and National Centers for Environmental Prediction/National Center for Atmospheric Research reanalysis climate variables (1948-2004) suggest that the Mt. Geladaindong ice core record provides a proxy for local and regional surface pressure. An approximately threefold decrease of soluble dust concentrations in the middle to late 1970s, accompanied by regional increases in pressure and temperature and decreases in wind velocity, coincides with the major 1976-1977 shift of the Pacific Decadal Oscillation (PDO) from a negative to a positive state. This is the first ice core evidence of a potential teleconnection between central Asian atmospheric soluble dust loading and the PDO. Analysis of temporally longer ice cores from Mt. Geladaindong may enhance understanding of the relationship between the PDO and central Asian atmospheric circulation and subsequent atmospheric soluble dust loading.

Selective uptake, distribution, and redistribution of Cd-109, Co-57, Zn-65, Ni-63, and Cs-134 via xylem and phloem in the heavy metal hyperaccumulator Solanum nigrum L

The focus of this article was to explore the translocation of Cd-109, Co-57, Zn-65, Ni-63, and Cs-134 via xylem and phloem in the newly found hyperaccumulator Solanum nigrum L. Two experiments with the uptake via the roots and transport of Cd-109, Co-57, and Zn-65 labeled by roots, and the redistribution of Cd-109, Zn-65, Co-57, Ni-63, and Cs-134 using flap label in S. nigrum in a hydroponic culture with a standard nutrient solution were conducted. The results showed that Cd-109 added for 24 h to the nutrient medium of young plants was rapidly taken up, transferred to the shoot, and accumulated in the cotyledons and the oldest leaves but was not efficiently redistributed within the shoot afterward leading to a rather low content in the fruits. In contrast, Co-57 was more slowly taken up and released to the shoot, but afterward, this element was redistributed from older leaves to younger leaves and maturing fruits. Zn-65 was rapidly taken up and transferred to the shoot (mainly to the youngest leaves and not to the cotyledons). Afterward, this radionuclide was redistributed within the shoot to the youngest organs and finally accumulated in the maturing fruits. After flap labeling, all five heavy metals tested (Cd-109, Co-57, Zn-65, Ni-63, Cs-134) were exported from the labeled leaf and redistributed within the plant. The accumulation in the fruits was most pronounced for Ni-63 and Zn-65, while a relatively high percentage of Co-57 was finally found in the roots. Cs-134 was roughly in the middle of them. The transport of Cd-109 differed from that previously reported for wheat or lupin and might be important for the potential of S. nigrum to hyperaccumulate cadmium.

Folate Receptor Targeted Alpha-Therapy Using Terbium-149

Terbium-149 is among the most interesting therapeutic nuclides for medical applications. It decays by emission of short-range α-particles (Eα = 3.967 MeV) with a half-life of 4.12 h. The goal of this study was to investigate the anticancer efficacy of a 149Tb-labeled DOTA-folate conjugate (cm09) using folate receptor (FR)-positive cancer cells in vitro and in tumor-bearing mice. 149Tb was produced at the ISOLDE facility at CERN. Radiolabeling of cm09 with purified 149Tb resulted in a specific activity of ~1.2 MBq/nmol. In vitro assays performed with 149Tb-cm09 revealed a reduced KB cell viability in a FR-specific and activity concentration-dependent manner. Tumor-bearing mice were injected with saline only (group A) or with 149Tb-cm09 (group B: 2.2 MBq; group C: 3.0 MBq). A significant tumor growth delay was found in treated animals resulting in an increased average survival time of mice which received 149Tb-cm09 (B: 30.5 d; C: 43 d) compared to untreated controls (A: 21 d). Analysis of blood parameters revealed no signs of acute toxicity to the kidneys or liver in treated mice over the time of investigation. These results demonstrated the potential of folate-based α-radionuclide therapy in tumor-bearing mice.

PEG spacers of different length influence the biological profile of bombesin-based radiolabeled antagonists

INTRODUCTION The gastrin-releasing peptide receptor (GRPR) was shown to be expressed with high density on several types of cancers. Radiolabeled peptides for imaging and targeted radionuclide therapy have been developed. In this study, we evaluated the potential of statine-based bombesin antagonists, conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) through oligoethyleneglycol spacers, labeled with (177)Lu and we determined the effect of polyethyleneglycol (PEG) spacer length on in vitro and in vivo properties. METHODS The bombesin antagonists were synthesized on solid phase using Fmoc chemistry; the spacers Fmoc-dPEGx-OH (x=2, 4, 6 and 12) and the DOTA(tBu)3 were coupled using a standard procedure. The peptides were labeled with (177)Lu and evaluated in vitro (lipophilicity, serum stability, internalization and binding affinity assays). Biodistribution studies were performed in PC-3 tumor-bearing nude mice. RESULTS The solid-phase synthesis was straightforward with an overall yield ranging from 30% to 35% based on the first Fmoc cleavage. The hydrophilicity increased with spacer length (logD: -1.95 vs -2.22 of PEG2 and PEG12 analogs, respectively). There is a tendency of increased serum stability by increasing the spacer length (T1/2=246±4 and 584±20 for PEG2 and PEG6 analogs, respectively) which seems to reverse with the PEG12 analog. The IC50 values are similar with the only significant difference of the PEG12 analog. The (177)Lu-labeled PEG4 and PEG6 conjugates showed similar pharmacokinetic with high tumor uptake and excellent tumor-to-kidney ratios (7.8 and 9.7 at 4h for the PEG4 and PEG6 derivatives, respectively). The pancreas uptake was relatively high at 1h but it shows fast washout (0.46%±0.02% IA/g and 0.29%±0.08% IA/g already at 4h). CONCLUSION Among all the studied analogs the PEG4 and PEG6 showed significantly better properties. The very high tumor-to-non-target organ ratios, in particular tumor-to-kidney ratios, already at early time point will be important in regard to safety concerning kidney toxicity.

Stereochemistry of Amino Acid Spacers Determines the Pharmacokinetics of (111)In-DOTA-Minigastrin Analogues for Targeting the CCK2/Gastrin Receptor.

The metabolic instability and high kidney retention of minigastrin (MG) analogues hamper their suitability for use in peptide-receptor radionuclide therapy of CCK2/gastrin receptor-expressing tumors. High kidney retention has been related to N-terminal glutamic acids and can be substantially reduced by coinjection of polyglutamic acids or gelofusine. The aim of the present study was to investigate the influence of the stereochemistry of the N-terminal amino acid spacer on the enzymatic stability and pharmacokinetics of (111)In-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-D) and (111)In-DOTA-(l-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-L). Using circular dichroism measurements, we demonstrate the important role of secondary structure on the pharmacokinetics of the two MG analogues. The higher in vitro serum stability together with the improved tumor-to-kidney ratio of the (d-Glu)6 congener indicates that this MG analogue might be a good candidate for further clinical study.

Wet and dry deposition of 129I in Seville (Spain) measured by accelerator mass spectrometry

Iodine-129 (Full-size image (<1 K)) concentrations have been determined by accelerator mass spectrometry in rainwater samples taken at Seville (southwestern Spain) in 1996 and 1997. This technique allows a reduction in the detection limits for this radionuclide in comparison to radiometric counting and other mass spectrometric methods such as ICP-MS. Typical 129I concentrations range from 4.7×107129I atoms/l (19.2%) to 4.97×109129I atoms/l (5.9%), while 129I depositions are normally in the order of 108–1010 atoms/m2 d. These values agree well with other results obtained for recent rainwater samples collected in Europe. Apart from these, the relationship between 129I deposition and some atmospheric factors has been analyzed, showing the importance of the precipitation rate and the concentration of suspended matter in it.

Analysis of iodine-129 in environmental materials: Quality assurance and applications

The long-lived radionuclide 129I (T 1/2 = 15.7 My) occurs in the nature in very low concentrations. Since the middle of our century the environmental levels of 129I have been dramatically changed as a consequence of civil and military use of nuclear fission. Its investigation in environmental materials is of interest for environmental surveillance, retrospective dosimetry and for the use as a natural and man-made fracers of environmental processes. We are comparing two analytical methods which presently are capable of determining 129I in environmental materials, namely radiochemical neutron activation analysis (RNAA) and accelerator mass spectrometry (AMS). Emphasis is laid upon the quality control and detection capabilities for the analysis of 129I in environmental materials. Some applications are discussed.

Cosmic-ray exposure ages of pallasites

We analyzed cosmogenic nuclides in metal and/or silicate (primarily olivine) separated from the main-group pallasites Admire, Ahumada, Albin, Brahin, Brenham, Esquel, Finmarken, Glorieta Mountain, Huckitta, Imilac, Krasnojarsk, Marjalahti, Molong, Seymchan, South Bend, Springwater, and Thiel Mountains and from Eagle Station. The metal separates contained an olivine fraction which although small, <1 wt% in most cases, nonetheless contributes significantly to the budgets of some nuclides (e.g., up to 35% for Ne-21 and Al-26). A correction for olivine is therefore essential and was made using model calculations and/or empirical relations for the production rates of cosmogenic nuclides in iron meteoroids and/or measured elemental concentrations. Cosmic-ray exposure (CRE) ages for the metal phases of the main-group pallasites range from 7 to 180 Ma, but many of the ages cluster around a central peak near 100 Ma. These CRE ages suggest that the parent body of the main-group pallasites underwent a major break-up that produced most of the meteorites analyzed. The CRE age distribution for the pallasites overlaps only a small fraction of the distribution for the IIIAB iron meteorites. Most pallasites and IIIAB irons originated in different collisions, probably on different parent bodies; a few IIIABs and pallasites may have come out of the same collision but a firm conclusion requires further study. CRE ages calculated from noble gas and radionuclide data of the metal fraction are higher on average than the Ne-21 exposure ages obtained for the olivine samples. As the metal and olivine fractions were taken in most cases from different specimens, the depth-dependency of the production rate ratio Be-10/Ne-21 in metal, not accounted for in our calculations, may explain the difference.

Geophysical logging on sediment core and hole CRP-3 from the Ross Sea, Antarctica

Cape Roberts drillhole CRP-3 in the northern part of McMurdo Sound (Ross Sea, Antarctica) targeted the western margin of the Victoria Land basin to investigate Neogene to Palaeogene climatic and tectonic history by obtaining continuous core and downhole logs (Cape Roberts Science Team, 2000). The CRP-3 drillhole extended to 939.42 mbsf (meters below seafloor) at a water depth of 297 m. The first downhole measurements after drilling were the temperature and salinity logs. Both were measured at the beginning and at the end of each of the three logging phases. Although an equilibrium temperature state may not have been fully reached after drilling, the temperature and salinity profiles seem to be scarcely disturbed. The average overall temperature gradient calculated from all temperature measurements is 28.5 K/km; remarkably lower than the temperature gradients found in other boreholes in the western Ross See and the Transantarctic Mountains. Anomalies in the salinity profiles at the beginning of each logging phase were no longer present at the end of the corresponding logging phase. This pattern indicates that drilling mud invaded the formation during drilling operations and flowed back into the borehole after drilling ceased. Thus, zones of temperature and salinity anomalies identify permeable zones in the formation and may be pathways for fluid flow. Radiogenic heat production, calculated from the radionuclide contents, is relatively low, with average values between 0.5 and 1.0 pW/m3. The highest values (up to 2 µW/m3) were obtained for the lower part of the Beacon Sandstone below 855 mbsf. The heat flow component due to radiogenic heat production integrated over the entire borehole is 0.7 mW/m2. Thermal conductivities range from 1.3 to 3 W/mK with an average value of 2.1 W/mK over the Tertiary section. Together with the average temperature gradient of 28.5 K/km this yields an average heat flow value of 60 mW/m2.

(Table 2) Annual mass fluxes, 230Th composition and organic geochemistry of sediment trap samples in the South Altantic

The scavenging of 231Pa and 230Th was investigated in the Atlantic Sector of the Southern Ocean by combining results from sediment trap and in situ filtration studies. We present the first high-resolution profile of dissolved 230Th and 231Pa in surface waters across the ACC, showing a dramatic southward increase of both radionuclides around the southern ACC Front at 533S. High dissolved 231Pa/230Th ratios combined with low 230Th/231Pa fractionation factors (F) in these surface waters result in extremely high 231Pa94/230Th94 ratios of material collected in the shallow traps. Particulate 231Pa94/230Th94 ratios in a shallow trap near Bouvet Island increase continuously during the productive period in austral summer, and drop back in the low flux period. This behavior, following the Rayleigh fractionation principle, is interpreted to be due to an increase in the dissolved 231Pa/230Th ratio in the euphotic zone resulting from preferential scavenging of 230Th relative to 231Pa, even in opal-dominated regions. In the post-bloom stage, the depleted radionuclide concentrations are replenished by upwelling of Circumpolar Deep Water. The high particulate 231Pa94/230Th94 signal is weakened during downward transport of the bloom particles in the water column by incorporation of deep suspended particles, which have a lower 231Pa94/230Th94 ratio. It is shown that under the special hydrographic conditions in the Southern Ocean scavenging from the upper water column significantly influences the budgets of 230Th and 231Pa in the sediment. Nevertheless, the budgets are still made up primarily by scavenging from the large standing stock of deep suspended particles.