Targets, Tracers and Translation – Novel Radiopharmaceuticals Boost Nuclear Medicine

This is the fourth Special Issue in Pharmaceuticals within the last six years dealing with aspects of radiopharmaceutical sciences. It demonstrates the significant interest and increasing relevance to ameliorate nuclear medicine imaging with PET or SPECT, and also radiotherapeutical procedures.Numerous targets and mechanisms have been identified and have been under investigation over the previous years, covering many fields of medical and clinical research. This development is well illustrated by the articles in the present issue, including 13 original research papers and one review, covering a broad range of actual research topics in the field of radiopharmaceutical sciences

Significant impact of different oxygen breathing conditions on noninvasive in vivo tumor-hypoxia imaging using [18F]-fluoro-azomycinarabino-furanoside ([18F]FAZA)

<p>Abstract</p> <p>Background</p> <p>[¹⁸F]FAZA is a PET biomarker with great potential for imaging tumor hypoxia. Aim of our study was to compare [¹⁸F]FAZA uptake in mice with subcutaneous exogenous CT26 colon carcinomas and endogenous polyoma middle-T (PyV-mT) mammary carcinomas and to analyze the influence of different breathing protocols in CT26 colon carcinomas as well as the reversibility or irreversibility of [¹⁸F]FAZA uptake.</p> <p>Methods</p> <p>We injected subcutaneous CT26 colon carcinoma or polyomavirus middle-T (PyV-mT) mammary carcinoma-bearing mice intravenously with¹⁸F-FAZA and performed PET scans 1-3 h post injection (<it>p.i.</it>). To analyze the impact of oxygen supply in CT26 carcinomas we used three different breathing protocols: (P0) air; (P1) 100% oxygen 1 h prior injection until 3 h <it>p.i.</it>; (P2) 100% oxygen breathing starting 2 min prior tracer injection until 1 h <it>p.i. </it>and during the PET scans; mice were breathing air between the 2 h and 3 h 10 min static scans. Normalized PET images were analyzed by using defined regions of interest. Finally, some mice were dissected for pimonidazole immunohistochemistry.</p> <p>Results</p> <p>There was no difference in¹⁸F-FAZA uptake 1-3 h <it>p.i. </it>between the two carcinoma types (CT26: 1.58 ± 0.45%ID/cc; PyV-mT: 1.47 ± 0.89%ID/cc, 1 h <it>p.i.</it>, tumor size < 0.5 cm³). We measured a significant tracer clearance, which was more pronounced in muscle tissue (P0). The [¹⁸F]FAZA tumor-to-muscle-ratios in CT26 colon carcinoma-bearing mice 2 h and 3 h, but not 1 h <it>p.i. </it>were significantly higher when the mice breathed air (P0: 3.56 ± 0.55, 3 h) compared to the oxygen breathing protocols (P1: 2.45 ± 0.58; P2: 2.77 ± 0.42, 3 h). Surprisingly, the breathing protocols P1 and P2 showed no significant differences in T/M ratios, thus indicating that the crucial [¹⁸F]FAZA uptake phase is during the first hour after [¹⁸F]FAZA injection. Importantly, the muscle clearance was not affected by the different oxygen breathing conditions while the tumor clearance was lower when mice were breathing air.</p> <p>Conclusion</p> <p>Exogenous CT26 colon carcinomas and endogenous polyoma middle-T (PyV-mT) mammary carcinomas showed no differences in [¹⁸F]FAZA uptake 1-3 h <it>p.i. </it>Our analysis using various breathing protocols with air (P0) and with pure oxygen (P1, P2) clearly indicate that [¹⁸F]FAZA is an appropriate PET biomarker for <it>in vivo </it>analysis of hypoxia revealing an enhanced tracer uptake in tumors with reduced oxygen supply. [¹⁸F]FAZA uptake was independent of tumor-type.</p

Cyclotrons Operated for Nuclear Medicine and Radiopharmacy in the German Speaking D-A-CH Countries: An Update on Current Status and Trends

Background: Cyclotrons form a central infrastructure and are a resource of medical radionuclides for the development of new radiotracers as well as the production and supply of clinically established radiopharmaceuticals for patient care in nuclear medicine. Aim: To provide an updated overview of the number and characteristics of cyclotrons that are currently in use within radiopharmaceutical sciences and for the development of radiopharmaceuticals to be used for patient care in Nuclear Medicine in Germany (D), Austria (A) and Switzerland (CH). Methods: Publicly available information on the cyclotron infrastructure was (i) consolidated and updated, (ii) supplemented by selective desktop research and, last but not least, (iii) validated by members of the committee of the academic “Working Group Radiochemistry and Radiopharmacy” (AGRR), consisting of radiochemists and radiopharmacists of the D-A-CH countries and belonging to the German Society of Nuclear Medicine (DGN), as well as the Radiopharmaceuticals Committee of the DGN. Results: In total, 42 cyclotrons were identified that are currently being operated for medical radionuclide production for imaging and therapy in Nuclear Medicine clinics, 32 of them in Germany, 4 in Austria and 6 in Switzerland. Two thirds of the cyclotrons reported (67%) are operated by universities, university hospitals or research institutions close to a university hospital, less by/in cooperation with industrial partners (29%) or a non-academic clinic/ PET-center (5%). Most of the cyclotrons (88%) are running with up to 18 MeV proton beams, which is sufficient for the production of the currently most common cyclotron-based radionuclides for PET imaging. Discussion: The data presented provide an academically-updated overview of the medical cyclotrons operated for the production of radiopharmaceuticals and their use in Nuclear Medicine in the D-A-CH countries. In this context, we discuss current developments and trends with a view to the cyclotron infrastructure in these countries, with a specific focus on organizational aspects

New pathogen-specific immunoPET/MR tracer for molecular imaging of a systemic bacterial infection

PublishedArticleThe specific and rapid detection of Enterobacteriaceae, the most frequent cause of gram-negative bacterial infections in humans, remains a major challenge. We developed a non-invasive method to rapidly detect systemic Yersinia enterocolitica infections using immunoPET (antibody-targeted positron emission tomography) with [64Cu]NODAGA-labeled Yersinia-specific polyclonal antibodies targeting the outer membrane protein YadA. In contrast to the tracer [18F]FDG, [64Cu]NODAGA-YadA uptake co-localized in a dose dependent manner with bacterial lesions of Yersinia-infected mice, as detected by magnetic resonance (MR) imaging. This was accompanied by elevated uptake of [64Cu]NODAGA-YadA in infected tissues, in ex vivo biodistribution studies, whereas reduced uptake was observed following blocking with unlabeled anti-YadA antibody. We show, for the first time, a bacteria-specific, antibody-based, in vivo imaging method for the diagnosis of a Gram-negative enterobacterial infection as a proof of concept, which may provide new insights into pathogen-host interactions.The research leading to these results has received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement n°602820, from the European Social Fund Baden-Württemberg (to SEA), and from the Deutsche Forschungsgemeinschaft (grant WI 3777/1-2; to SW)

Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage

INTRODUCTION: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. METHODS: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. HIGHLIGHTS: Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage

Positron emission tomography and magnetic resonance imaging methods and datasets within the Dominantly Inherited Alzheimer Network (DIAN)

The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case-control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual's point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of 'sporadic' AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers

Positron emission tomography and magnetic resonance imaging methods and datasets within the dominantly inherited Alzheimer network (DIAN)

The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case–control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual’s point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of ‘sporadic’ AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers

Special Issue “Targets, Tracers and Translation Novel Radiopharmaceuticals Boost Nuclear Medicine”

This is the fourth Special Issue in Pharmaceuticals within the last six years dealing with aspects of radiopharmaceutical sciences [...]</jats:p

Special Issue “Targets, Tracers and Translation Novel Radiopharmaceuticals Boost Nuclear Medicine”

This is the fourth Special Issue in Pharmaceuticals within the last six years dealing with aspects of radiopharmaceutical sciences [...