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Aim: Targeted radionuclide therapy with Th-227 conjugated with novel antibodies, e.g. CD33 and CD70 has been pre-clinically used for treatment of myeloid leukaemia and renal cell carcinoma, respectively. Furthermore, PSMA-targeted Th-227 conjugate PSMA- TTC was recently developed for preclinical pharmacological study of treatment of prostate cancer. The imaging of alpha-emitter labelled radiopharmaceuticals in clinical practice is challenging. Therefore theoretical modelling of bio-distributions of Th-227 and its immediate decay product Ra-223 and other progeny is highly desired. Especially radiolabelled metabolites or unconjugated daughters may lead to toxicity but also might be beneficial in the case of unconjugated Ra-223 targeting metastatic bone lesions. Materials and methods: The current ICRP systemic biokinetic model structure and transfer parameters of thorium were taken as the prior model and parameters for pharmacokinetic modelling. Because the immediate decay product Ra-223 is another high LET alpha-emitter which can potentially be toxic to healthy tissues, the biokinetic model of radium was coupled to that for Th-227. By doing so, the bio-distributions of Th-227 and Ra-223 in human body can be simultaneously monitored. Furthermore, other decay products were as well taken into account and connected to Ra-223 as independent biokinetic models. Results: Model predictions show that 67% of Th-227 leaves blood with a clearance half-life of 6 h and deposits on the bone surface, 6% of Th-227 deposits in the liver and 4.5% of Th-227 deposits in the kidneys. The progeny Ra-223 deposits a similar activity in the alimentary tract and in the liver as the parent Th-227. The retentions of Ra-223 as progeny in kidneys and testes are about 8% of that of parent Th-227. Conclusion: The modelled pharmacokinetic bio-distributions of Th-227 and its decay products can be used as start distributions for local kinetic analysis, such as bone surface, volume, marrow and blood. The bio-distributions of decay products can be further used for patient dosimetry assessments.

Bone metastases, often a consequence of breast, prostate, and lung carcinomas, are characterized by an increased bone turnover, which can be visualized by positron emission tomography (PET), as well as single-photon emission computed tomography (SPECT). Bisphosphonate complexes of 99mTc are predominantly used as SPECT tracers. In contrast to SPECT, PET offers a higher spatial resolution and, owing to the 68Ge/68Ga generator, an analog to the established 99mTc generator exists. Complexation of Ga(III) requires the use of chelators. Therefore, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), NOTA (1,4,7-triazacyclododecane-1,4,7-triacetic acid), and their derivatives, are often used. The combination of these macrocyclic chelators and bisphosphonates is currently studied worldwide. The use of DOTA offers the possibility of a therapeutic application by complexing the β-emitter 177Lu. This overview describes the possibility of diagnosing bone metastases using [68Ga]Ga-BPAMD (68Ga-labeled (4-{[bis-(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid) as well as the successful application of [177Lu]Lu-BPAMD for therapy and the development of new diagnostic and therapeutic tools based on this structure. Improvements concerning both the chelator and the bisphosphonate structure are illustrated providing new 68Ga- and 177Lu-labeled bisphosphonates offering improved pharmacological properties.

Hopes for a new abundance of diverse media content have long been tied to the rise of the Internet. Ensuring diversity remains a fundamental objective of media policy. However, media policy is still largely focused on public service media. In this article, we introduce a new theoretical perspective to inform media policy, focusing on the concept of diversity experience and users' motivation, awareness, and ability to seek diverse content in a transforming media environment. We argue that our understanding of and regulatory approaches to media pluralism must be adapted to technological advances. Based on social cognitive theory, we propose an extension of the diversity debate by considering user cognition. We analyze challenges to users' diversity experiences on a motivational, perceptual, and capability level. Given the (over)abundance of content available online, users must be willing and able to seek out diverse and serendipitous information. We derive a user-centric approach to media pluralism and diversity. Based on this framework, we outline criteria for changing the role of public service media in the digital age to focus on empowering users to actually experience media diversity.

Bone metastases are a class of cancerous metastases that result from the invasion of a tumor into bone. The solid mass which forms inside the bone is often associated with a constant dull ache and severe spikes in pain, which greatly reduce the quality of life of the patient. Numerous 99mTc-labeled bisphosphonate functionalised complexes are well established tracers for bone metastases imaging. The objective of this research was to evaluate the pharmacokinetics and behaviour of three DOTA based bisphosphonate functionalised ligands (BPAMD, BPAPD and BPPED), using both 68Ga μ-PET in vivo imaging and ex vivo biodistribution studies in healthy Wistar rats. The compounds were labelled with 68Ga in high yields using an ammonium acetate buffer, and subsequently purified using a cation exchange resin. High bone uptake values were observed for all 68Ga-labelled bisphosphonates at 60 minutes p.i. The highest uptake was observed for [68Ga]BPPED (2.6 ± 0.3% ID/g) which compares favourably with that of [99mTc]MDP (2.7 ± 0.1 ID/g) and [18F]fluoride (2.4 ± 0.2% ID/g). The 68Ga-labelled DOTA-bisphosphonates showed rapid clearance from the blood and renal system, as well as low binding to soft tissue, resulting in a high bone to blood ratio (9.9 at 60 minutes p.i. for [68Ga]BPPED, for example). Although further studies are required to assess their performance in tumor models, the results obtained suggest that these ligands could be useful both in imaging (68Ga) and therapeutic treatment (177Lu) of bone metastases.

We propose a new approach to obtain molecular frame photoelectron angular distributions from molecules ionized by intense laser pulses. With our method we study the angular tunnel ionization probability of H2 at a wavelength of 800 nm over an intensity range of 2–4.5×1014 W/cm2. We find an anisotropy that is stronger than predicted by any existing model. To explain the observed anisotropy and its strong intensity dependence we develop an analytical model in the framework of the strong-field approximation. It expresses molecular ionization as a product of atomic ionization rate and a Fourier transform of the highest occupied molecular orbital filtered by the strong-field ionization process.

Aim: Main indications of oncologic skeletal imaging are metastatic diseases in skeleton, bone pain in patients with known cancer, and primary bone tumors. Benign bone diseases like pediatric/adult back pain, bone viability and Paget's disease are also important indications of skeletal imaging. There are numerous studies with [18F]fluoride PET demonstrating the clinical utility. Similar characteristics show Tc-99m-labeled bisphosphonates. Combining the bone seeking properties, the advantages of PET, and the potential labeling with therapeutic radionuclides we studied DOTA-phosphonates radiolabeled with [68Ga]Ga3+. Methods: The following macrocyclic tetraaza based phosphonate chelators were used BPAMD ((4-{[(bis-phosphonomethyl) carbomoyl]methyl}-7,10-bis-(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)-acetic acid, BPAPD ((4-{[(bis-phosphonopropyl)carbomoyl]methyl}-7,10-bis-(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)-acetic acid and BPPED Tetraethyl 10-{[(2,2-bis-phosphonoethyl)hydroxyphosphoryl]methyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid. The DOTA based phosphonate ligands were labeled with [68Ga]GaCl3. The radiochemical purity of the labeled products was >95% determined with radio thin-layer chromatography. The biodistribution and biokinetics were compared with [18F]fluoride and [99mTc]Tc-MDP in Wistar rats using dissection, small animal PET and SPECT. All activity concentration data were calculated as SUV. Results: The compounds were labeled with high yields in ammonium acetate buffer with 68Ga, followed by a purification step using a cation exchange resin. High uptake values were detected for all 68Ga-phosphonates in the femura. The accumulation of [68Ga]BPPED in the bone was the highest and comparable with the uptake of [18F]Fluoride and [99mTc]Tc-MDP. The blood clearance of the [68Ga]BPPED was the fastest with a biexponential kinetics and half-life of 0.4 min and 6.9 min. The [68Ga]BPPED bone to blood ratio was also superior, however, not so large like of [18F]Fluoride and [99mTc]Tc-MDP. Conclusion: The [68Ga]BPPED showed in a preclinical setting excellent characteristics for skeletal imaging. It seems to be also a potential candidate for radionuclide therapy in oncology.

Aim: Main indications of oncologic skeletal imaging are metastatic diseases in skeleton, bone pain in patients with known cancer, and primary bone tumors. Benign bone diseases like pediatric/adult back pain, bone viability and Paget’s disease are also important indications of skeletal imaging. There are numerous studies with [18F]fluoride PET demonstrating the clinical utility. Similar characteristics show Tc-99m-labeled bisphosphonates. Combining the bone seeking properties, the advantages of PET, and the potential labeling with therapeutic radionuclides we studied DOTA-phosphonates radiolabeled with [68Ga]Ga3+. Methods: The following macrocyclic tetraaza based phosphonate chelators were used BPAMD ((4–{[(bis-phosphonomethyl) carbomoyl]methyl}–7,10–bis–(carboxymethyl)–1,4,7,10-tetraazacyclododec–1–yl)–acetic acid, BPAPD ((4–{[(bis–phosphonopropyl)carbomoyl]methyl}–7,10–bis–(carboxymethyl)–1,4,7,10-tetraazacyclododec–1–yl)–acetic acid and BPPED Tetraethyl 10-{[(2,2-bis-phosphonoethyl)hydroxyphosphoryl]methyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid. The DOTA based phosphonate ligands were labeled with [68Ga]GaCl3. The radiochemical purity of the labeled products was >95% determined with radio thin-layer chromatography. The biodistribution and biokinetics were compared with [18F]fluoride and [99mTc]Tc-MDP in Wistar rats using dissection, small animal PET and SPECT. All activity concentration data were calculated as SUV. Results: The compounds were labeled with high yields in ammonium acetate buffer with 68Ga, followed by a purification step using a cation exchange resin. High uptake values were detected for all 68Ga-phosphonates in the femura. The accumulation of [68Ga]BPPED in the bone was the highest and comparable with the uptake of [18F]Fluoride and [99mTc]Tc-MDP. The blood clearance of the [68Ga]BPPED was the fastest with a biexponential kinetics and half-life of 0.4 min and 6.9 min. The [68Ga]BPPED bone to blood ratio was also superior, however, not so large like of [18F]Fluoride and [99mTc]Tc-MDP. Conclusion: The [68Ga]BPPED showed in a preclinical setting excellent characteristics for skeletal imaging. It seems to be also a potential candidate for radionuclide therapy in oncology

Background: Metastatic bone lesion is a common syndrome of many cancer diseases in an advanced state. The major symptom is severe pain, spinal cord compression, and pathological fracture, associated with an obvious morbidity. Common treatments including systemic application of bisphosphonate drugs aim on pain reduction and on improving the quality of life of the patient. Particularly, patients with multiple metastatic lesions benefit from bone-targeting therapeutic radiopharmaceuticals. Agents utilizing beta-emitting radionuclides in routine clinical praxis are, for example, [89Sr]SrCl2 and [153Sm]Sm-EDTMP. No-carrier-added (n.c.a.) 177Lu is remarkably suitable for an application in this scope. Methods: Five 1,4,7,10-tetraazacyclododecane N,N',N'',N''-tetra-acetic acid (DOTA)- and DO2A-based bisphosphonates, including monomeric and dimeric structures and one 1,4,7-triazacyclononane-1,4-diacetic acid (NO2A) derivative, were synthesized and labelled with n.c.a. 177Lu. Radio-TLC and high-performance liquid chromatography (HPLC) methods were successfully established for determining radiochemical yields and for quality control. Their binding to hydroxyapatite was measured in vitro. Ex vivo biodistribution experiments and dynamic in vivo single photon computed tomography (SPECT)/CT measurements were performed in healthy rats for 5 min and 1 h periods. Data on %ID/g or standard uptake value (SUV) for femur, blood, and soft-tissue organs were analyzed and compared with [177Lu]citrate. Results: Radiolabelling yields for [177Lu]Lu-DOTA and [177Lu]Lu-NO2A monomeric bisphosphonate complexes were >98 % within 15 min. The dimeric macrocyclic bisphosphonates showed a decelerated labelling kinetics, reaching a plateau after 30 min of 60 to 90 % radiolabelling yields. All 177Lu-bisphosphonate complexes showed exclusive accumulation in the skeleton. Blood clearance and renal elimination were fast. SUV data (all for 1 h p.i.) in the femur ranged from 3.34 to 5.67. The bone/blood ratios were between 3.6 and 135.6, correspondingly. 177Lu-bisphosphonate dimers showed a slightly higher bone accumulation (SUVfemur = 4.48 ± 0.38 for [177Lu] Lu-DO2A(PBP)2; SUVfemur = 5.41 ± 0.46 for [177Lu]Lu-DOTA(MBP)2) but a slower blood clearance (SUVblood = 1.25 ± 0.09 for [177Lu]Lu-DO2A(PBP)2; SUVblood = 1.43 ± 0.32 for [177Lu]Lu-DOTA(MBP)2). Conclusions: Lu-complexes of macrocyclic bisphosphonates might become options for the therapy of skeletal metastases in the near future, since they show high uptake in bone together with a very low soft-tissue accumulation.