Observation of the radiative decay of the 229Th nuclear clock isomer.

The radionuclide thorium-229 features an isomer with an exceptionally low excitation energy that enables direct laser manipulation of nuclear states. It constitutes one of the leading candidates for use in next-generation optical clocks1-3. This nuclear clock will be a unique tool for precise tests of fundamental physics4-9. Whereas indirect experimental evidence for the existence of such an extraordinary nuclear state is substantially older10, the proof of existence has been delivered only recently by observing the isomer's electron conversion decay11. The isomer's excitation energy, nuclear spin and electromagnetic moments, the electron conversion lifetime and a refined energy of the isomer have been measured12-16. In spite of recent progress, the isomer's radiative decay, a key ingredient for the development of a nuclear clock, remained unobserved. Here, we report the detection of the radiative decay of this low-energy isomer in thorium-229 (229mTh). By performing vacuum-ultraviolet spectroscopy of 229mTh incorporated into large-bandgap CaF2 and MgF2 crystals at the ISOLDE facility at CERN, photons of 8.338(24) eV are measured, in agreement with recent measurements14-16 and the uncertainty is decreased by a factor of seven. The half-life of 229mTh embedded in MgF2 is determined to be 670(102) s. The observation of the radiative decay in a large-bandgap crystal has important consequences for the design of a future nuclear clock and the improved uncertainty of the energy eases the search for direct laser excitation of the atomic nucleus.

Tuning the Framework of Thioether-Functionalized Polyazamacrocycles: Searching for a Chelator for Theranostic Silver Radioisotopes.

Silver-111 is an attractive unconventional candidate for targeted cancer therapy as well as for single photon emission computed tomography and can be complemented by silver-103 for positron emission tomography noninvasive diagnostic procedures. However, the shortage of chelating agents capable of forming stable complexes tethered to tumor-seeking vectors has hindered their in vivo application so far. In this study, a comparative investigation of a series of sulfur-containing structural homologues, namely, 1,4,7-tris[2-(methylsulfanyl)ethyl)]-1,4,7-triazacyclononane (NO3S), 1,5,9-tris[2-(methylsulfanyl)ethyl]-1,5,9-triazacyclododecane (TACD3S), 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclotridecane (TRI4S), and 1,4,8,11-tetrakis[2-(methylsulfanyl)ethyl]-1,4,8,11-tetraazacyclotetradecane (TE4S) was conducted to appraise the influence of different polyazamacrocyclic backbones on Ag+ complexation. The performances of these macrocycles were also compared with those of the previously reported Ag+/[111Ag]Ag+-chelator 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S). Nuclear magnetic resonance data supported by density functional theory calculations and X-ray crystallographic results gave insights into the coordination environment of these complexes, suggesting that all of the donor atoms are generally involved in the metal coordination. However, the modifications of the macrocycle topology alter the dynamic binding of the pendant arms or the conformation of the ring around the metal center. Combined pH/pAg-potentiometric and spectroscopic experiments revealed that the 12-member N4 backbone of DO4S forms the most stable Ag+ complex while both the enlargement and the shrinkage of the macrocyclic frame dwindle the stability of the complexes. Radiolabeling experiments, conducted with reactor-produced [111Ag]Ag+, evidenced that the thermodynamic stability trend is reflected in the ligand's ability to incorporate the radioactive ion at high molar activity, even in the presence of a competing cation (Pd2+), as well as in the integrity of the corresponding complexes in human serum. As a consequence, DO4S proved to be the most favorable candidate for future in vivo applications.

Tying Up a Loose End: On the Role of the C-Terminal CCHHRAG Fragment of the Metalloregulator CueR.

The transcriptional regulator CueR is activated by the binding of CuI , AgI , or AuI to two cysteinates in a near-linear fashion. The C-terminal CCHHRAG sequence in Escherichia coli CueR present potential additional metal binding ligands and here we explore the effect of deleting this fragment on the binding of AgI to CueR. CD spectroscopic and ESI-MS data indicate that the high AgI -binding affinity of WT-CueR is significantly reduced in Δ7C-CueR.[111 Ag PAC spectroscopy demonstrates that the WT-CueR metal site structure (AgS2 ) is conserved, but less populated in the truncated variant. Thus, the function of the C-terminal fragment may be to stabilize the two-coordinate metal site for cognate monovalent metal ions. In a broader perspective this is an example of residues beyond the second coordination sphere affecting metal site physicochemical properties while leaving the structure unperturbed.

Combination of terbium-161 with somatostatin receptor antagonists-a potential paradigm shift for the treatment of neuroendocrine neoplasms.

PURPOSE: The ߯-emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs). METHODS: The capability of the 161Tb- and 177Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides' tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively. RESULTS: In vitro, [161Tb]Tb-DOTA-LM3 was 102-fold more potent than [177Lu]Lu-DOTA-LM3; however, 161Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their 177Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [161Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [177Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy. CONCLUSION: The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [161Tb]Tb-DOTA-LM3 may outperform the clinically employed [177Lu]Lu-DOTATOC for the treatment of patients with NENs.

Flexibility of the CueR Metal Site Probed by Instantaneous Change of Element and Oxidation State from AgI to CdII.

Selectivity for monovalent metal ions is an important facet of the function of the metalloregulatory protein CueR. 111 Ag perturbed angular correlation of γ-rays (PAC) spectroscopy probes the metal site structure and the relaxation accompanying the instantaneous change from AgI to CdII upon 111 Ag radioactive decay. That is, a change from AgI , which activates transcription, to CdII , which does not. In the frozen state (-196 °C) two nuclear quadrupole interactions (NQIs) are observed; one (NQI1 ) agrees well with two coordinating thiolates and an additional longer contact to the S77 backbone carbonyl, and the other (NQI2 ) reflects that CdII has attracted additional ligand(s). At 1 °C only NQI2 is observed, demonstrating that relaxation to this structure occurs within ≈10 ns of the decay of 111 Ag. Thus, transformation from AgI to CdII rapidly disrupts the functional linear bis(thiolato)AgI metal site structure. This inherent metal site flexibility may be central to CueR function, leading to remodelling into a non-functional structure upon binding of non-cognate metal ions. In a broader perspective, 111 Ag PAC spectroscopy may be applied to probe the flexibility of protein metal sites.

Highly Stable Silver(I) Complexes with Cyclen-Based Ligands Bearing Sulfide Arms: A Step Toward Silver-111 Labeled Radiopharmaceuticals.

With a half-life of 7.45 days, silver-111 (ßmax 1.04 MeV, Eγ 245.4 keV [Iγ 1.24%], Eγ 342.1 keV [Iγ 6.7%]) is a promising candidate for targeted cancer therapy with ß- emitters as well as for associated SPECT imaging. For its clinical use, the development of suitable ligands that form sufficiently stable Ag+-complexes in vivo is required. In this work, the following sulfur-containing derivatives of tetraazacyclododecane (cyclen) have been considered as potential chelators for silver-111: 1,4,7,10-tetrakis(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO4S), (2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10-tetrakis(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO4S4Me), 1,4,7-tris(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris(2-(methylsulfanyl)ethyl)-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis(2-(methylsulfanyl)ethyl)-4,10,diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S). Natural Ag+ was used in pH/Ag-potentiometric and UV-vis spectrophotometric studies to determine the metal speciation existing in aqueous NaNO3 0.15 M at 25 °C and the equilibrium constants of the complexes, whereas NMR and DFT calculations gave structural insights. Overall results indicated that sulfide pendant arms coordinate Ag+ allowing the formation of very stable complexes, both at acidic and physiological pH. Furthermore, radiolabeling, stability in saline phosphate buffer, and metal-competition experiments using the two ligands forming the strongest complexes, DO4S and DO4S4Me, were carried out with [111Ag]Ag+ and promising results were obtained.

High-resolution laser resonance ionization spectroscopy of 143 - 147 Pm.

We present the results of high-resolution laser spectroscopy of the long-lived radioactive isotopes 143 - 147 Pm. The hyperfine structures and isotope shifts in two different atomic ground-state transitions at 452 nm and 468 nm were probed by in-source laser spectroscopy at the RISIKO mass separator in Mainz, using the PI-LIST ion source. From the hyperfine coupling constants the nuclear magnetic dipole and electric quadrupole moments for 143 - 147 Pm were derived, and the measured isotope shifts allowed the extraction of changes in nuclear mean square charge radii.

Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer.

PURPOSE: The prostate-specific membrane antigen (PSMA) has emerged as an interesting target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). The aim of this study was to investigate 161Tb (T1/2 = 6.89 days; Eß͞av = 154 keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to 177Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile. METHODS: 161Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100 MBq/nmol. 161Tb-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for 177Lu-PSMA-617. The effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells. 161Tb-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice. RESULTS: 161Tb-PSMA-617 and 177Lu-PSMA-617 displayed equal in-vitro properties and tissue distribution profiles in tumor-bearing mice. The viability and survival of PC-3 PIP tumor cells were more reduced when exposed to 161Tb-PSMA-617 as compared to the effect obtained with the same activities of 177Lu-PSMA-617 over the whole investigated concentration range. Treatment of mice with 161Tb-PSMA-617 (5.0 MBq/mouse and 10 MBq/mouse, respectively) resulted in an activity-dependent increase of the median survival (36 vs 65 days) compared to untreated control animals (19 days). Therapy studies to compare the effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 indicated the anticipated superiority of 161Tb over 177Lu. CONCLUSION: 161Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to 177Lu-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of 161Tb. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of 161Tb-PSMA-617 for the treatment of mCRPC.

Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model.

PURPOSE: The L1 cell adhesion molecule (L1CAM) is considered a valuable target for therapeutic intervention in different types of cancer. Recent studies have shown that anti-L1CAM radioimmunotherapy (RIT) with (67)Cu- and (177)Lu-labelled internalising monoclonal antibody (mAb) chCE7 was effective in the treatment of human ovarian cancer xenografts. In this study, we directly compared the therapeutic efficacy of anti-L1CAM RIT against human ovarian cancer under equitoxic conditions with the radiolanthanide (177)Lu and the potential alternative (161)Tb in an ovarian cancer therapy model. METHODS: Tb was produced by neutron bombardment of enriched (160)Gd targets. (161)Tb and (177)Lu were used for radiolabelling of DOTA-conjugated antibodies. The in vivo behaviour of the radioimmunoconjugates (RICs) was assessed in IGROV1 tumour-bearing nude mice using biodistribution experiments and SPECT/CT imaging. After ascertaining the maximal tolerated doses (MTD) the therapeutic impact of 50 % MTD of (177)Lu- and (161)Tb-DOTA-chCE7 was evaluated in groups of ten mice by monitoring the tumour size of subcutaneous IGROV1 tumours. RESULTS: The average number of DOTA ligands per antibody was 2.5 and maximum specific activities of 600 MBq/mg were achieved under identical radiolabelling conditions. RICs were stable in human plasma for at least 48 h. (177)Lu- and (161)Tb-DOTA-chCE7 showed high tumour uptake (37.8-39.0 %IA/g, 144 h p.i.) with low levels in off-target organs. SPECT/CT images confirmed the biodistribution data. (161)Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the (177)Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the (161)Tb-DOTA-chCE7 than the (177)Lu-DOTA-chCE7 RIT. CONCLUSIONS: Our study is the first to show that anti-L1CAM (161)Tb RIT is more effective compared to (177)Lu RIT in ovarian cancer xenografts. These results suggest that (161)Tb is a promising candidate for future clinical applications in combination with internalising antibodies.

Cs-131 as an experimental tool for the investigation and quantification of the radiotoxicity of intracellular Auger decays in vitro.

PURPOSE: In this work, we set out to provide an experimental setup, using Cs-131, with associated dosimetry for studying relative biological effectiveness (RBE) of Auger emitters. MATERIAL AND METHODS: Cs-131 decays by 100% electron capture producing K- (9%) and L- (80%) Auger electrons with mean energies of 26 keV and 3.5 keV, respectively, plus ≈ 9.4 very low energy electrons (<0.5 keV) per decay. Cs-131 accumulates in the cells through the Na+/K+-ATPase. By this uptake mechanism and the alkali chemistry of Cs+, we argue for its intracellular homogeneous distribution. Cs-131 was added to the cell culture medium of HeLa and V79 Cells. The bio-kinetics of Cs-131 (uptake, release, intracellular distribution) was examined by measuring its intracellular activity concentration over time. Taking advantage of the 100% confluent cellular monolayer, we developed a new and robust dosimetry that is entrusted to a quantity called SC-value. RESULTS: The SC-values evaluated in the cell nucleus are almost independent of the nuclear size and geometry. We obtained dose-rate controlled RBE-values for intracellular Cs-131 decay. Using the γH2AX assay, the RBE was 1 for HeLa cells. Using the clonogenic cell survival, it was 3.9 for HeLa cells and 3.2 for V79 cells. CONCLUSION: This experimental setup and dosimetry provides reliable RBE-values for Auger emitters in various cell lines.

161Tb-DOTATOC Production Using a Fully Automated Disposable Cassette System: A First Step Toward the Introduction of 161Tb into the Clinic.

161Tb is an interesting radionuclide for application in the treatment of neuroendocrine neoplasms' small metastases and single cancer cells because of its conversion and Auger-electron emission. Tb has coordination chemistry similar to that of Lu; therefore, like 177Lu, it can stably radiolabel DOTATOC, one of the leading peptides used for the treatment of neuroendocrine neoplasms. However, 161Tb is a recently developed radionuclide that has not yet been specified for clinical use. Therefore, the aim of the current work was to characterize and specify 161Tb and to develop a protocol for the synthesis and quality control of 161Tb-DOTATOC with a fully automated process conforming to good-manufacturing-practice guidelines, in view of its clinical use. Methods: 161Tb, produced by neutron irradiation of 160Gd in high-flux reactors followed by radiochemical separation from its target material, was characterized regarding its radionuclidic purity, chemical purity, endotoxin level, and radiochemical purity (RCP) in analogy to what is described in the European Pharmacopoeia for no-carrier-added 177Lu. In addition, 161Tb was introduced into a fully automated cassette-module synthesis to produce 161Tb-DOTATOC, as used for 177Lu-DOTATOC. The quality and stability of the produced radiopharmaceutical in terms of identity, RCP, and ethanol and endotoxin content were assessed by means of high-performance liquid chromatography, gas chromatography, and an endotoxin test, respectively. Results: 161Tb produced under the described conditions showed, as the no-carrier-added 177Lu, a pH of 1-2, radionuclidic purity and RCP of more than 99.9%, and an endotoxin level below the permitted range (175 IU/mL), indicating its appropriate quality for clinical use. In addition, an efficient and robust procedure for the automated production and quality control of 161Tb-DOTATOC with clinically applicable specifications and activity levels, that is, 1.0-7.4 GBq in 20 mL, was developed. The radiopharmaceutical's quality control was also developed using chromatographic methods, which confirmed the product's stability (RCP ≥ 95%) over 24 h. Conclusion: The current study demonstrated that 161Tb has appropriate features for clinical use. The developed synthesis protocol guarantees high yields and safe preparation of injectable 161Tb-DOTATOC. The investigated approach could be translated to other DOTA-derivatized peptides; thus, 161Tb could be successfully applied in clinical practice for radionuclide therapy.

Measurement of the 171Tm beta spectrum.

The beta spectrum of the main transition of the ß- decay of 171Tm was measured using a double focalizing spectrometer. The instrument was lately improved in order to reduce its low energy threshold to 34 keV. We used the spectrometer to measure the beta spectrum end-point energy of the main transition of 171Tm decay using the Kurie plot formalism. We report a new value of 97.60(38) keV, which is in agreement with previous measurements. In addition, the spectrum shape was compared with the ξ-approximation calculation where the shape factor is equal to 1 and good agreement was found between the theory and the measurement at the 1% level.

Albumin-Binding and Conventional PSMA Ligands in Combination with 161Tb: Biodistribution, Dosimetry, and Preclinical Therapy.

The favorable decay characteristics of 161Tb attracted the interest of clinicians in using this novel radionuclide for radioligand therapy (RLT). 161Tb decays with a similar half-life to 177Lu, but beyond the emission of ß--particles and γ-rays, 161Tb also emits conversion and Auger electrons, which may be particularly effective to eliminate micrometastases. The aim of this study was to compare the dosimetry and therapeutic efficacy of 161Tb and 177Lu in tumor-bearing mice using SibuDAB and PSMA-I&T, which differ in their blood residence time and tumor uptake. Methods: [161Tb]Tb-SibuDAB and [161Tb]Tb-PSMA-I&T were evaluated in vitro and investigated in biodistribution, imaging, and therapy studies using PC-3 PIP tumor-bearing mice. The 177Lu-labeled counterparts served for dose calculations and comparison of therapeutic efficacy. The tolerability of RLT in mice was monitored on the basis of body mass, blood plasma parameters, blood cell counts, and the histology of relevant organs and tissues. Results: The prostate-specific membrane antigen (PSMA)-targeting radioligands, irrespective of whether labeled with 161Tb or 177Lu, showed similar in vitro data and comparable tissue distribution profiles. As a result of the albumin-binding properties, [161Tb]Tb/[177Lu]Lu-SibuDAB had an enhanced blood residence time and higher tumor uptake (62%-69% injected activity per gram at 24 h after injection) than [161Tb]Tb/[177Lu]Lu-PSMA-I&T (30%-35% injected activity per gram at 24 h after injection). [161Tb]Tb-SibuDAB inhibited tumor growth more effectively than [161Tb]Tb-PSMA-I&T, as can be ascribed to its 4-fold increased absorbed tumor dose. At any of the applied activities, the 161Tb-based radioligands were therapeutically more effective than their 177Lu-labeled counterparts, as agreed with the approximately 40% increased tumor dose of 161Tb compared with that of 177Lu. Under the given experimental conditions, no obvious adverse events were observed. Conclusion: The data of this study indicate the promising potential of 161Tb in combination with SibuDAB for RLT of prostate cancer. Future clinical studies using 161Tb-based RLT will shed light on a potential clinical benefit of 161Tb over 177Lu.

Towards in vivo applications of 111Ag perturbed angular correlation of γ-rays (PAC) spectroscopy.

111Ag-perturbed angular correlation of γ-rays (PAC) spectroscopy provides information on the nuclear quadrupole interactions, and thereby on the local structure and dynamics of the silver ion binding site. Brownian rotational motion, i.e. rotational diffusion, of 111Ag-labeled molecules will significantly affect the PAC spectra. Here we illustrate this effect, by simulating 111Ag PAC spectra for 111Ag-labeled molecules with molecular masses spanning from 102 to 106 g/mol, reflecting a span from fast (small molecules) to slow (large molecules) rotational diffusion on the PAC time scale. The simulated spectra are compared to 111Ag-PAC data obtained from a pilot study involving 111Ag(I) bound to a designed chelator exhibiting fast reorientation in solution, as well as to 111Ag-labeled species formed by 111Ag(I) in human serum, exhibiting slow (or no) reorientation on the PAC time scale. The simulated and experimental data illustrate typical PAC signals that are likely to be observed in vivo, when following the fate of 111Ag-labeled compounds. Potential in vivo applications are stability studies of 111Ag-radiopharmaceuticals, dissociation studies of 111Ag from the labeled molecule followed by binding to another (bio)molecule, or binding of 111Ag-labeled probes to larger carriers such as proteins.

Revised rates for the stellar triple-alpha process from measurement of 12C nuclear resonances.

In the centres of stars where the temperature is high enough, three alpha-particles (helium nuclei) are able to combine to form 12C because of a resonant reaction leading to a nuclear excited state. (Stars with masses greater than approximately 0.5 times that of the Sun will at some point in their lives have a central temperature high enough for this reaction to proceed.) Although the reaction rate is of critical significance for determining elemental abundances in the Universe, and for determining the size of the iron core of a star just before it goes supernova, it has hitherto been insufficiently determined. Here we report a measurement of the inverse process, where a 12C nucleus decays to three alpha-particles. We find a dominant resonance at an energy of approximately 11 MeV, but do not confirm the presence of a resonance at 9.1 MeV (ref. 3). We show that interference between two resonances has important effects on our measured spectrum. Using these data, we calculate the triple-alpha rate for temperatures from 10(7) K to 10(10) K and find significant deviations from the standard rates. Our rate below approximately 5 x 10(7) K is higher than the previous standard, implying that the critical amounts of carbon that catalysed hydrogen burning in the first stars are produced twice as fast as previously believed. At temperatures above 10(9) K, our rate is much less, which modifies predicted nucleosynthesis in supernovae.

Ytterbium-175 half-life determination.

175Yb is a radionuclide that can be generated by neutron capture on 174Yb and whose decay properties make it useful for developing therapeutic radiopharmaceuticals. As it happens with many of the emerging radionuclides for medical uses in recent years, its nuclear data were determined decades ago and are not thoroughly documented nor accurate enough for metrological purposes. The last documented reference for the 175Yb half-life value is 4.185(1) days and dates back to 1989, so a redetermination of the value was considered appropriate before standardization at the Institute of Radiation Physics (IRA, Lausanne, Switzerland) primary measurements laboratory. Three independent measurement methods were used to this purpose: reference ionization chamber (CIR, chambre d'ionization de référence), CeBr3 γ-ray detector with digital electronics and a second CeBr3 detector with analog electronics and single-channel analyzer (SCA) counting. The value obtained for the 175Yb half-life is 4.1615(30) days which shows a 0.56% relative deviation to the last nuclear reference value (ENSDF 2004) and is supported with a detailed calculation of the associated uncertainty.

Effective Intratumoral Retention of [103 Pd]AuPd Alloy Nanoparticles Embedded in Gel-Forming Liquids Paves the Way for New Nanobrachytherapy.

Local application of radioactive sources as brachytherapy is well established in oncology. This treatment is highly invasive however, due to the insertion of millimeter sized metal seeds. The authors report the development of a new concept for brachytherapy, based on gold-palladium (AuPd) alloy nanoparticles, intrinsically radiolabeled with 103 Pd. These are formulated in a carbohydrate-ester based liquid, capable of forming biodegradable gel-like implants upon injection. This allows for less invasive administration through small-gauge needles. [103 Pd]AuPd nanoparticles with sizes around 20 nm are prepared with radiolabeling efficiencies ranging from 79% to >99%. Coating with the hydrophobic polymer poly(N-isopropylacrylamide) leads to nanoparticle diameters below 40 nm. Dispersing the nanoparticles in ethanol with water insoluble carbohydrate esters gives "nanogels", a low viscosity liquid capable of solidifying upon injection into aqueous environments. Both nanoparticles and radioactivity are stably retained in the nanogel over 25 days (>99%) after formation in aqueous buffers. Animals bearing CT26 murine tumors are injected intratumorally with 25 MBq of the 103 Pd-nanogel, and display tumor growth delay and significantly increase median survival times compared with control groups. Excellent retention in the tumor of both the 103 Pd and the nanoparticle matrix itself is observed, demonstrating a potential for replacing currently used brachytherapy seeds.

Simultaneous Visualization of 161Tb- and 177Lu-Labeled Somatostatin Analogues Using Dual-Isotope SPECT Imaging.

The decay of terbium-161 results in the emission of ߯-particles as well as conversion and Auger electrons, which makes terbium-161 interesting for therapeutic purposes. The aim of this study was to use dual-isotope SPECT imaging in order to demonstrate visually that terbium-161 and lutetium-177 are interchangeable without compromising the pharmacokinetic profile of the radiopharmaceutical. The 161Tb- and 177Lu-labeled somatostatin (SST) analogues DOTATOC (agonist) and DOTA-LM3 (antagonist) were tested in vitro to demonstrate equal properties regarding distribution coefficients and cell uptake into SST receptor-positive AR42J tumor cells. The radiopeptides were further investigated in AR42J tumor-bearing nude mice using the method of dual-isotope (terbium-161/lutetium-177) SPECT/CT imaging to enable the visualization of their distribution profiles in the same animal. Equal pharmacokinetic profiles were demonstrated for either of the two peptides, irrespective of whether it was labeled with terbium-161 or lutetium-177. Moreover, the visualization of the sub-organ distribution confirmed similar behavior of 161Tb- and 177Lu-labeled SST analogues. The data were verified in quantitative biodistribution studies using either type of peptide labeled with terbium-161 or lutetium-177. While the radionuclide did not have an impact on the organ distribution, this study confirmed previous data of a considerably higher tumor uptake of radiolabeled DOTA-LM3 as compared to the radiolabeled DOTATOC.

Production cross-section measurements of proton-induced reactions on natural tantalum in the 0.3 GeV-1.7 GeV energy range.

This work reports the production cross-section data for seventy-one radionuclides produced by 0.3 GeV-1.7 GeV protons impinging on thin tantalum targets. For that purpose, activation experiments were performed using the COSY synchrotron at FZ Jülich utilizing the stacked-foils technique and γ-ray spectrometry with high-purity germanium detectors. The Al-27(p,x)Na-24 reaction has been used as monitor reaction. All experimental data have been systematically compared with the existing literature. The excitation functions of Te-116, I-123, Dy-153 and Er-158 are reported for the first time.

First-in-Humans Application of 161Tb: A Feasibility Study Using 161Tb-DOTATOC.

161Tb has decay properties similar to those of 177Lu but, additionally, emits a substantial number of conversion and Auger electrons. The aim of this study was to apply 161Tb in a clinical setting and to investigate the feasibility of visualizing the physiologic and tumor biodistributions of 161Tb-DOTATOC. Methods:161Tb was shipped from Paul Scherrer Institute, Villigen-PSI, Switzerland, to Zentralklinik Bad Berka, Bad Berka, Germany, where it was used for the radiolabeling of DOTATOC. In 2 separate studies, 596 and 1,300 MBq of 161Tb-DOTATOC were administered to a 35-y-old male patient with a metastatic, well-differentiated, nonfunctional malignant paraganglioma and a 70-y-old male patient with a metastatic, functional neuroendocrine neoplasm of the pancreatic tail, respectively. Whole-body planar γ-scintigraphy images were acquired over a period of several days for dosimetry calculations. SPECT/CT images were reconstructed using a recently established protocol and visually analyzed. Patients were observed for adverse events after the application of 161Tb-DOTATOC. Results: The radiolabeling of DOTATOC with 161Tb was readily achieved with a high radiochemical purity suitable for patient application. Planar images and dosimetry provided the expected time-dependent biodistribution of 161Tb-DOTATOC in the liver, kidneys, spleen, and urinary bladder. SPECT/CT images were of high quality and visualized even small metastases in bones and liver. The application of 161Tb-DOTATOC was well tolerated, and no related adverse events were reported. Conclusion: This study demonstrated the feasibility of imaging even small metastases after the injection of relatively low activities of 161Tb-DOTATOC using γ-scintigraphy and SPECT/CT. On the basis of this essential first step in translating 161Tb to clinics, further efforts will be directed toward the application of 161Tb for therapeutic purposes.