Novel radionuclides for use in Nuclear Medicine in Europe: where do we stand and where do we go?

BACKGROUND: In order to support the ongoing research across Europe to facilitate access to novel radionuclides, the PRISMAP consortium (European medical radionuclides programme) was established to offer the broadest catalog of non-conventional radionuclides for medical and translational research. The aim of this article is to introduce readers with current status of novel radionuclides in Europe. MAIN BODY: A consortium questionnaire was disseminated through the PRISMAP consortium and user community, professional associations and preclinical/clinical end users in Europe and the current status of clinical end-users in nuclear medicine were identified. A total of 40 preclinical/clinical users institutions took part in the survey. Clinical end users currently use the following radionuclides in their studies: 177Lu, 68 Ga, 111In, 90Y, other alpha emitters, 225Ac, 64Cu and Terbium isotopes. Radionuclides that would be of interest for users within the next 2-5 years are 64Cu, Terbium radionuclide "family" and alpha emitters, such as 225Ac. CONCLUSIONS: Thanks to a questionnaire distributed by the PRISMAP consortium, the current status and needs of clinical end-users in nuclear medicine were identified.

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.

Improved procedures for production and purification of 135La from enriched [135Ba]BaCO3 on a 16.5 MeV cyclotron.

Lanthanum-135 (135La) is a favorable Auger electron emitter with a high Auger electron yield and low gamma emission, making it promising for Auger electron radiotherapy. However, successful application requires reliable and scalable 135La production. Up to now, metallic natural barium (natBa) is a commonly used target material, but this material is sensitive to moisture and oxidation. BaCO3 has also been tested, due to its higher chemical stability. However, BaCO3 has poor thermal conductivity, limiting the applicable current and making high yield production challenging. In this study, we pressed a mixture of enriched [135Ba]BaCO3 and fine aluminum (Al) powder to provide a stable target with improved thermal conductivity compared to pure BaCO3. After 4 h of irradiation with a 16.5 MeV proton beam at 20 µA current, 1.62 ± 0.18 GBq was produced from a 200 mg [135Ba]BaCO3:Al (1:2, w/w) target. This corresponded to a saturation yield of 11.91 ± 1.31 GBq (or 596 ± 66 MBq/µA). A purification procedure involving initial precipitation, followed by a single composite column containing a layer of TK200 resin and a second layer of branched DGA resin was developed, with 97.1 ± 3.6 % decay corrected 135La recovery. [135La]LaCl3 was obtained in an effective molar activity of 79.6 ± 25.3 MBq/nmol (DOTA titration), 104.0 ± 40.4 MBq/nmol (DTPA titration) and 186.5 ± 83.8 MBq/nmol (CHX-A″-DTPA titration), and a radionuclidic purity (RNP) of >99.9 % at end of purification, hereby demonstrating a purity suitable for radiopharmaceutical use.

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.

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.

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.

Multi-curie production of gallium-68 on a biomedical cyclotron and automated radiolabelling of PSMA-11 and DOTATATE.

BACKGROUND: With increasing clinical demand for gallium-68, commercial germanium-68/gallium-68 ([68Ge]Ge/[68Ga]Ga) generators are incapable of supplying sufficient amounts of the short-lived daughter isotope. In this study, we demonstrate a high-yield, automated method for producing multi-Curie levels of [68Ga]GaCl3 from solid zinc-68 targets and subsequent labelling to produce clinical-grade [68Ga]Ga-PSMA-11 and [68Ga]Ga-DOTATATE. RESULTS: Enriched zinc-68 targets were irradiated at up to 80 µA with 13 MeV protons for 120 min; repeatedly producing up to 194 GBq (5.24 Ci) of purified gallium-68 in the form of [68Ga]GaCl3 at the end of purification (EOP) from an expected > 370 GBq (> 10 Ci) at end of bombardment. A fully automated dissolution/separation process was completed in 35 min. Isolated product was analysed according to the Ph. Eur. monograph for accelerator produced [68Ga]GaCl3 and found to comply with all specifications. In every instance, the radiochemical purity exceeded 99.9% and importantly, the radionuclidic purity was sufficient to allow for a shelf-life of up to 7 h based on this metric alone. Fully automated production of up to 72.2 GBq [68Ga]Ga-PSMA-11 was performed, providing a product with high radiochemical purity (> 98.2%) and very high apparent molar activities of up to 722 MBq/nmol. Further, manual radiolabelling of up to 3.2 GBq DOTATATE was performed in high yields (> 95%) and with apparent molar activities (9-25 MBq/nmol) sufficient for clinical use. CONCLUSIONS: We have developed a high-yielding, automated method for the production of very high amounts of [68Ga]GaCl3, sufficient to supply proximal radiopharmacies. The reported method led to record-high purified gallium-68 activities (194 GBq at end of purification) and subsequent labelling of PSMA-11 and DOTATATE. The process was highly automated from irradiation through to formulation of the product, and as such comprised a high level of radiation protection. The quality control results obtained for both [68Ga]GaCl3 for radiolabelling and [68Ga]Ga-PSMA-11 are promising for clinical use.

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.

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.

A solid support generator of the Auger electron emitter rhodium-103m from [103Pd]palladium.

Auger electron therapy is an attractive modality for targeting microscopic tumors. Rhodium-103 m (103mRh, T½â€¯= 56.1 min) is a promising Auger electron emitter that can be obtained as the decay product of palladium-103 (103Pd, T½â€¯= 16.99 days). 103Pd was chelated in a lipophilic derivative of the 16aneS4 macrocycle and the complex was trapped on a C18 cartridge. Elution with dilute hydrochloric acid gave radiochemically pure 103mRh. We hypothesize this to be through a combination of the Szilard-Chalmers effect and transient ionization.

Cell colony counter called CoCoNut.

Clonogenic assays are powerful tools for testing cell reproductive death after biological damage caused by, for example, ionizing radiation. Traditionally, the methods require a cumbersome, slow and eye-straining manual counting of viable colonies under a microscope. To speed up the counting process and minimize those issues related to the subjective decisions of the scoring personnel, we developed a semi-automated, image-based cell colony counting setup, named CoCoNut (Colony Counter developed by the Nutech department at the Technical University of Denmark). It consists in an ImageJ macro and a photographic 3D-printed light-box, conceived and demonstrated to work together for Crystal Violet-stained colonies. Careful attention was given to the image acquisition process, which allows background removal (i.e. any unwanted element in the picture) in a minimally invasive manner. This is mainly achieved by optimal lighting conditions in the light-box and dividing the image of a flask that contains viable colonies by the picture of an empty flask. In this way, CoCoNut avoids using aggressive background removal filters that usually lead to suboptimal colony count recovery. The full method was tested with V79 and HeLa cell survival samples. Results were compared to other freely available tools. CoCoNut proved able to successfully distinguish between single and merged colonies and to identify colonies bordering on flask edges. CoCoNut software calibration is fast; it requires the adjustment of a single parameter that is the smallest colony area to be counted. The employment of a single parameter reduces the risk of subjectivity, providing a robust and user-friendly tool, whose results can be easily compared over time and among different bio-laboratories. The method is inexpensive and easy to obtain. Among its advantages, we highlight the possibility of combining the macro with a perfectly reproducible 3D-printed light-box. The CoCoNut software and the 3D-printer files are provided as supporting information (S1 CoCoNut Files).

Evolution of the Biosynthetic Pathway for Cyanogenic Glucosides in Lepidoptera.

Cyanogenic glucosides are widespread defence compounds in plants, and they are also found in some arthropods, especially within Lepidoptera. The aliphatic linamarin and lotaustralin are the most common cyanogenic glucosides in Lepidoptera, and they are biosynthesised de novo, and/or sequestered from food plants. Their biosynthetic pathway was elucidated in the burnet moth, Zygaena filipendulae, and consists of three enzymes: two cytochrome P450 enzymes, CYP405A2 and CYP332A3, and a glucosyl transferase, UGT33A1. Heliconius butterflies also produce linamarin and lotaustralin and have close homologs to CYP405A2 and CYP332A3. To unravel the evolution of the pathway in Lepidoptera, we performed phylogenetic analyses on all available CYP405 and CYP332 sequences. CYP332 sequences were present in almost all Lepidoptera, while the distribution of CYP405s among butterflies and moths was much more limited. Negative purifying selection was found in both CYP enzyme families, indicating that the biosynthesis of CNglcs is an old trait, and not a newly evolved pathway. We compared CYP405A2 to its close paralog, CYP405A3, which is not involved in the biosynthetic pathway. The only significant difference between these two enzymes is a smaller substrate binding pocket in CYP405A2, which would make the enzyme more substrate specific. We consider it likely that the biosynthetic pathway of CNglcs in butterflies and moths have evolved from a common pathway, perhaps based on a predisposition for detoxifying aldoximes by way of a CYP332. Later the aldoxime metabolising CYP405s evolved, and a UGT was recruited into the pathway to establish de novo biosynthesis of CNglcs.

Structure of Radical-Induced Cell Death1 Hub Domain Reveals a Common αα-Scaffold for Disorder in Transcriptional Networks.

Communication within cells relies on a few protein nodes called hubs, which organize vast interactomes with many partners. Frequently, hub proteins are intrinsically disordered conferring multi-specificity and dynamic communication. Conversely, folded hub proteins may organize networks using disordered partners. In this work, the structure of the RST domain, a unique folded hub, is solved by nuclear magnetic resonance spectroscopy and small-angle X-ray scattering, and its complex with a region of the transcription factor DREB2A is provided through data-driven HADDOCK modeling and mutagenesis analysis. The RST fold is unique, but similar structures are identified in the PAH (paired amphipathic helix), TAFH (TATA-box-associated factor homology), and NCBD (nuclear coactivator binding domain) domains. We designate them as a group the αα hubs, as they share an αα-hairpin super-secondary motif, which serves as an organizing platform for malleable helices of varying topology. This allows for partner adaptation, exclusion, and selection. Our findings provide valuable insights into structural features enabling signaling fidelity.

Radiobiological effects of tritiated water short-term exposure on V79 clonogenic cell survival.

PURPOSE: We set out to improve the accuracy of absorbed dose calculations for in vitro measurements of the relative biological effectiveness (RBE) of tritiated water (HTO) for the clonogenic cell survival assay, also considering the influence of the end-of-track linear energy transfer (LET) of low-energy electrons. MATERIALS AND METHODS: The COmputation Of Local Electron Release (COOLER) program was adopted to investigate the cell geometry and the tritium full beta-decay spectrum impact on the S-values and subsequently on the RBE of HTO for clonogenic cell survival at similar high dose rates (HDR). RESULTS: S-values for cells growing in suspension are usually comparable to those for adherent cells. RBEs calculated at the 10% survival fraction through the use of the average energy are almost similar to those obtained with the beta-spectrum. For adherent cells, an RBE of 1.6 was found when HTO cell survival curves were compared to acute γ-ray exposures. Irrespective of the geometrical configuration, the RBE was 2.0 when the comparison was made with similar dose rates. CONCLUSIONS: These results underline the importance of irradiating at equal dose rates and cell culture conditions when measuring in vitro RBE-values.

Towards Translational ImmunoPET/MR Imaging of Invasive Pulmonary Aspergillosis: The Humanised Monoclonal Antibody JF5 Detects Aspergillus Lung Infections In Vivo.

Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of hematological malignancy or bone marrow transplant patients caused by the ubiquitous environmental fungus Aspergillus fumigatus. Current diagnostic tests for the disease lack sensitivity as well as specificity, and culture of the fungus from invasive lung biopsy, considered the gold standard for IPA detection, is slow and often not possible in critically ill patients. In a previous study, we reported the development of a novel non-invasive procedure for IPA diagnosis based on antibody-guided positron emission tomography and magnetic resonance imaging (immunoPET/MRI) using a [64Cu]DOTA-labeled mouse monoclonal antibody (mAb), mJF5, specific to Aspergillus. To enable translation of the tracer to the clinical setting, we report here the development of a humanised version of the antibody (hJF5), and pre-clinical imaging of lung infection using a [64Cu]NODAGA-hJF5 tracer. The humanised antibody tracer shows a significant increase in in vivo biodistribution in A. fumigatus infected lungs compared to its radiolabeled murine counterpart [64Cu]NODAGA-mJF5. Using reverse genetics of the pathogen, we show that the antibody binds to the antigenic determinant ß1,5-galactofuranose (Galf) present in a diagnostic mannoprotein antigen released by the pathogen during invasive growth in the lung. The absence of the epitope Galf in mammalian carbohydrates, coupled with the enhanced imaging capabilities of the hJF5 antibody, means that the [64Cu]NODAGA-hJF5 tracer developed here represents an ideal candidate for the diagnosis of IPA and translation to the clinical setting.

Spatial separation of the cyanogenic ß-glucosidase ZfBGD2 and cyanogenic glucosides in the haemolymph of Zygaena larvae facilitates cyanide release.

Low molecular weight compounds are typically used by insects and plants for defence against predators. They are often stored as inactive ß-glucosides and kept separate from activating ß-glucosidases. When the two components are mixed, the ß-glucosides are hydrolysed releasing toxic aglucones. Cyanogenic plants contain cyanogenic glucosides and release hydrogen cyanide due to such a well-characterized two-component system. Some arthropods are also cyanogenic, but comparatively little is known about their system. Here, we identify a specific ß-glucosidase (ZfBGD2) involved in cyanogenesis from larvae of Zygaena filipendulae (Lepidoptera, Zygaenidae), and analyse the spatial organization of cyanide release in this specialized insect. High levels of ZfBGD2 mRNA and protein were found in haemocytes by transcriptomic and proteomic profiling. Heterologous expression in insect cells showed that ZfBGD2 hydrolyses linamarin and lotaustralin, the two cyanogenic glucosides present in Z. filipendulae. Linamarin and lotaustralin as well as cyanide release were found exclusively in the haemoplasma. Phylogenetic analyses revealed that ZfBGD2 clusters with other insect ß-glucosidases, and correspondingly, the ability to hydrolyse cyanogenic glucosides catalysed by a specific ß-glucosidase evolved convergently in insects and plants. The spatial separation of the ß-glucosidase ZfBGD2 and its cyanogenic substrates within the haemolymph provides the basis for cyanide release in Z. filipendulae. This spatial separation is similar to the compartmentalization of the two components found in cyanogenic plant species, and illustrates one similarity in cyanide-based defence in these two kingdoms of life.

The COOLER Code: A Novel Analytical Approach to Calculate Subcellular Energy Deposition by Internal Electron Emitters.

COmputation Of Local Electron Release (COOLER), a software program has been designed for dosimetry assessment at the cellular/subcellular scale, with a given distribution of administered low-energy electron-emitting radionuclides in cellular compartments, which remains a critical step in risk/benefit analysis for advancements in internal radiotherapy. The software is intended to overcome the main limitations of the medical internal radiation dose (MIRD) formalism for calculations of cellular S-values (i.e., dose to a target region in the cell per decay in a given source region), namely, the use of the continuous slowing down approximation (CSDA) and the assumption of a spherical cell geometry. To this aim, we developed an analytical approach, entrusted to a MATLAB-based program, using as input simulated data for electron spatial energy deposition directly derived from full Monte Carlo track structure calculations with PARTRAC. Results from PARTRAC calculations on electron range, stopping power and residual energy versus traveled distance curves are presented and, when useful for implementation in COOLER, analytical fit functions are given. Example configurations for cells in different culture conditions (V79 cells in suspension or adherent culture) with realistic geometrical parameters are implemented for use in the tool. Finally, cellular S-value predictions by the newly developed code are presented for different cellular geometries and activity distributions (uniform activity in the nucleus, in the entire cell or on the cell surface), validated against full Monte Carlo calculations with PARTRAC, and compared to MIRD standards, as well as results based on different track structure calculations (Geant4-DNA). The largest discrepancies between COOLER and MIRD predictions were generally found for electrons between 25 and 30 keV, where the magnitude of disagreement in S-values can vary from 50 to 100%, depending on the activity distribution. In calculations for activity distribution on the cell surface, MIRD predictions appeared to fail the most. The proposed method is suitable for Auger-cascade electrons, but can be extended to any energy of interest and to beta spectra; as an example, the 3H case is also discussed. COOLER is intended to be accessible to everyone (preclinical and clinical researchers included), and may provide important information for the selection of radionuclides, the interpretation of radiobiological or preclinical results, and the general establishment of doses in any scenario, e.g., with cultured cells in the laboratory or with therapeutic or diagnostic applications. The software will be made available for download from the DTU-Nutech website: http://www.nutech.dtu.dk/ .

Experimental implementation and proof of principle for a radionuclidic purity test solely based on half-life measurement.

In this paper we present the results of an experimental implementation of the method (Jørgensen et al., 2012) for testing the radionuclidic purity (RNP) of F-18 compounds. The overall limitations of the experimental methods and their possible impacts on RNP detectability have been identified. We have developed an GUI application for use as an easy and automated test tool in the production procedure. The test results show that this method fully complies with the requirements in the European Pharmacopoeia (Eur. Ph.) for RNP of FDG and F-18 Sodium Fluoride.

PET/CT Based In Vivo Evaluation of 64Cu Labelled Nanodiscs in Tumor Bearing Mice.

64Cu radiolabelled nanodiscs based on the 11 α-helix MSP1E3D1 protein and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine lipids were, for the first time, followed in vivo by positron emission tomography for evaluating the biodistribution of nanodiscs. A cancer tumor bearing mouse model was used for the investigations, and it was found that the approximately 13 nm nanodiscs, due to their size, permeate deeply into cancer tissue. This makes them promising candidates for both drug delivery purposes and as advanced imaging agents. For the radiolabelling, a simple approach for 64Cu radiolabelling of proteins via a chelating agent, DOTA, was developed. The reaction was performed at sufficiently mild conditions to be compatible with labelling of the protein part of a lipid-protein particle while fully conserving the particle structure including the amphipathic protein fold.

Improved methods to determine radionuclidic purity of F-18 compounds.

Current revisions of monographs for F-18 pharmaceuticals in the European Pharmacopoeia (Ph. Eur.) (Ph. Eur., 2011) call for a radionuclidic purity (RNP) of or better than 99.9%. However, the current method is not sufficient nor effective for testing this required RNP level. We present a theoretical model leading to a practical procedure for a simple test of RNP for F-18 compounds that tells whether or not the sample is pure with a statistical confidence of 97.5% (P=0.975).