Molecular imaging in atherosclerosis

Atherosclerosis is the major cause of cardiovascular disease, which still has the leading position in morbidity and mortality in the Western world. Many risk factors and pathobiological processes are acting together in the development of atherosclerosis. This leads to different remodelling stages (positive and negative) which are both associated with plaque physiology and clinical presentation. The different remodelling stages of atherosclerosis are explained with their clinical relevance. Recent advances in basic science have established that atherosclerosis is not only a lipid storage disease, but that also inflammation has a fundamental role in all stages of the disease. The molecular events leading to atherosclerosis will be extensively reviewed and described. Further on in this review different modalities and their role in the different stages of atherosclerosis will be discussed. Non-nuclear invasive imaging techniques (intravascular ultrasound, intravascular MRI, intracoronary angioscopy and intravascular optical coherence tomography) and non-nuclear non-invasive imaging techniques (ultrasound with Doppler flow, electron-bean computed tomography, coronary computed tomography angiography, MRI and coronary artery MR angiography) will be reviewed. After that we focus on nuclear imaging techniques for detecting atherosclerotic plaques, divided into three groups: atherosclerotic lesion components, inflammation and thrombosis. This emerging area of nuclear imaging techniques can provide measures of biological activity of atherosclerotic plaques, thereby improving the prediction of clinical events. As we will see in the future perspectives, at present, there is no special tracer that can be called the diagnostic tool to diagnose prospective stroke or infarction in patients. Nevertheless, we expect such a tracer to be developed in the next few years and maybe, theoretically, it could even be used for targeted therapy (in the form of a beta-emitter) to combat cardiovascular disease

Radiopharmaceuticals for imaging chronic lymphocytic inflammation

In the last few decades, a number of radiopharmaceuticals for imaging inflammation have been proposed that differ in their specificity and mechanism of uptake in inflamed foci as compared to the traditional inflammation imaging agents. Radiolabelled cytokines represent a reliable tool for the preclinical diagnosis of chronic inflammatory processes, even before anatomical and functional changes occur in affected tissues. Moreover, the introduction of radiolabelled monoclonal antibodies and sophisticated technique like PET/CT now make the field of inflammation imaging highly specific and accurate. In this review, different approaches of the established and experimental radiopharmaceuticals for imaging of chronic inflammation are discussed.Nas últimas décadas, foram propostos vários radiofármacos para obtenção de imagens de sítios de inflamação, diferindo em suas especificidades e mecanismos de captação quando comparados aos tradicionais agentes utilizados para essa finalidade. Citocinas radiomarcadas representam uma ferramenta confiável para o diagnóstico pré-clinico precoce de processos inflamatórios crônicos, anterior às alterações anatômicas e funcionais, em tecidos afetados. Além disso, a introdução de anticorpos monoclonais radiomarcados e técnicas sofisticadas, como PET/CT, tornaram a obtenção de imagens de focos de inflamação altamente específica e apurada. Nesta revisão, diferentes abordagens com radiofármacos já bem estabelecidos e com outros em nível experimental para a obtenção de imagens de sítios de inflamação crônica são discutidas

Pharmacokinetic properties of radiolabeled mutant Interleukin-2v:a PET imaging study

Interleukin-2 (IL2) is a cytokine that can stimulate cytotoxic immune cells to attack infected and malignant cells. Unfortunately, IL2 can also cause serious immune-related toxicity. Recently, a mutant of IL2 (IL2v) with abolished CD25 binding, increased plasma half-life and less toxicity was engineered. Unlike wild-type IL2 (wt-IL2), mutant IL2v does not bind to the α-subunit (CD25) of the high affinity IL2αβγ receptor, but only to its β and γ subunit. Here, we investigated the biological properties of IL2v and compared with the wt-IL2 using fluorine-18 and PET. [18F]FB-IL2v binds specifically to IL2 receptors (IL2R) on activated human peripheral blood monocytes (hPBMCs) and is cleared mainly by the kidneys (Balb/c mice). [18F]FB-IL2v PET studies in SCID mice injected with hPBMCs revealed high uptake in the implant (0.85 ± 0.15 SUV), which was significantly reduced after pretreatment with wt-IL2 or mutant IL2v (SUV 0.26 ± 0.1 and 0.46 ± 0.1,p< 0.01). Compartment modeling and Logan graphical analysis in wistar rats inoculated with hPBMCs indicated that the binding of [18F]FB-IL2v to IL2R was reversible. The volume of distribution (VT) and the non-displaceable binding potential (BPnd) of mutant [18F]FB-IL2v in the implant were approximately 3 times lower than those of wild-type [18F]FB-IL2 (p< 0.01). Pretreatment with wt-IL2 significantly reduced the VTand BPnd of mutant [18F]FB-IL2v in the implant (p< 0.001). This demonstrates that wild-type [18F]FB-IL2 binds stronger to IL2R and has faster kinetics than [18F]FB-IL2v, which makes it less suitable as a therapeutic drug. [18F]FB-IL2v, on the other hand, seems to have better properties for use as a therapeutic drug

Synthesis and Evaluation of 99mTc-Labelled Monoclonal Antibody 1D09C3 for Molecular Imaging of Major Histocompatibility Complex Class II Protein Expression

Purpose: It is known that major histocompatibility complex class II protein HLA-DR is highly expressed in B-cell lymphomas and in a variety of autoimmune and inflammatory diseases. Therefore, a radiolabelled fully humanized IgG4 monoclonal antibody (mAb) can provide useful prognostic and diagnostic information. Aims of the present study were to radiolabel an anti-HLA-DR mAb with technetium-99m and to evaluate its binding specificity, tissue distribution and targeting potential. Procedures: For labelling, we compared a direct method, after 2-mercaptoethanol (2-ME) reduction of disulphide bonds, with a two-step labelling method, using a heterobifunctional succinimidyl-6-hydrazinonicotinate hydrochloride chelator. Several in vitro quality controls and in vivo experiments in mice were performed. Results: We obtained highest labelling efficiency (LE, 998%) and specific activity (SA; 5,550 MBq/mg) via the direct method. In vitro quality control showed good stability, structural integrity and retention of the binding properties of the labelled mAb. The biodistribution in mice showed high and persistent uptake in spleen and suggests kidney and liver-mediated clearanc

European Association of Nuclear Medicine Focus 5: Consensus on Molecular Imaging and Theranostics in Prostate Cancer

BACKGROUND In prostate cancer (PCa), questions remain on indications for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging and PSMA radioligand therapy, integration of advanced imaging in nomogram-based decision-making, dosimetry, and development of new theranostic applications. OBJECTIVE We aimed to critically review developments in molecular hybrid imaging and systemic radioligand therapy, to reach a multidisciplinary consensus on the current state of the art in PCa. DESIGN, SETTING, AND PARTICIPANTS The results of a systematic literature search informed a two-round Delphi process with a panel of 28 PCa experts in medical or radiation oncology, urology, radiology, medical physics, and nuclear medicine. The results were discussed and ratified in a consensus meeting. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Forty-eight statements were scored on a Likert agreement scale and six as ranking options. Agreement statements were analysed using the RAND appropriateness method. Ranking statements were analysed using weighted summed scores. RESULTS AND LIMITATIONS After two Delphi rounds, there was consensus on 42/48 (87.5%) of the statements. The expert panel recommends PSMA PET to be used for staging the majority of patients with unfavourable intermediate and high risk, and for restaging of suspected recurrent PCa. There was consensus that oligometastatic disease should be defined as up to five metastases, even using advanced imaging modalities. The group agreed that [$^{177}$Lu]Lu-PSMA should not be administered only after progression to cabazitaxel and that [$^{223}$Ra]RaCl$_{2}$ remains a valid therapeutic option in bone-only metastatic castration-resistant PCa. Uncertainty remains on various topics, including the need for concordant findings on both [$^{18F}$]FDG and PSMA PET prior to [$^{177}$Lu]Lu-PSMA therapy. CONCLUSIONS There was a high proportion of agreement among a panel of experts on the use of molecular imaging and theranostics in PCa. Although consensus statements cannot replace high-certainty evidence, these can aid in the interpretation and dissemination of best practice from centres of excellence to the wider clinical community. PATIENT SUMMARY There are situations when dealing with prostate cancer (PCa) where both the doctors who diagnose and track the disease development and response to treatment, and those who give treatments are unsure about what the best course of action is. Examples include what methods they should use to obtain images of the cancer and what to do when the cancer has returned or spread. We reviewed published research studies and provided a summary to a panel of experts in imaging and treating PCa. We also used the research summary to develop a questionnaire whereby we asked the experts to state whether or not they agreed with a list of statements. We used these results to provide guidance to other health care professionals on how best to image men with PCa and what treatments to give, when, and in what order, based on the information the images provide

European Association of Nuclear Medicine Focus 5:Consensus on Molecular Imaging and Theranostics in Prostate Cancer

BACKGROUND: In prostate cancer (PCa), questions remain on indications for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging and PSMA radioligand therapy, integration of advanced imaging in nomogram-based decision-making, dosimetry, and development of new theranostic applications.OBJECTIVE: We aimed to critically review developments in molecular hybrid imaging and systemic radioligand therapy, to reach a multidisciplinary consensus on the current state of the art in PCa.DESIGN, SETTING, AND PARTICIPANTS: The results of a systematic literature search informed a two-round Delphi process with a panel of 28 PCa experts in medical or radiation oncology, urology, radiology, medical physics, and nuclear medicine. The results were discussed and ratified in a consensus meeting.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Forty-eight statements were scored on a Likert agreement scale and six as ranking options. Agreement statements were analysed using the RAND appropriateness method. Ranking statements were analysed using weighted summed scores.RESULTS AND LIMITATIONS: After two Delphi rounds, there was consensus on 42/48 (87.5%) of the statements. The expert panel recommends PSMA PET to be used for staging the majority of patients with unfavourable intermediate and high risk, and for restaging of suspected recurrent PCa. There was consensus that oligometastatic disease should be defined as up to five metastases, even using advanced imaging modalities. The group agreed that [177Lu]Lu-PSMA should not be administered only after progression to cabazitaxel and that [223Ra]RaCl2 remains a valid therapeutic option in bone-only metastatic castration-resistant PCa. Uncertainty remains on various topics, including the need for concordant findings on both [18F]FDG and PSMA PET prior to [177Lu]Lu-PSMA therapy.CONCLUSIONS: There was a high proportion of agreement among a panel of experts on the use of molecular imaging and theranostics in PCa. Although consensus statements cannot replace high-certainty evidence, these can aid in the interpretation and dissemination of best practice from centres of excellence to the wider clinical community.PATIENT SUMMARY: There are situations when dealing with prostate cancer (PCa) where both the doctors who diagnose and track the disease development and response to treatment, and those who give treatments are unsure about what the best course of action is. Examples include what methods they should use to obtain images of the cancer and what to do when the cancer has returned or spread. We reviewed published research studies and provided a summary to a panel of experts in imaging and treating PCa. We also used the research summary to develop a questionnaire whereby we asked the experts to state whether or not they agreed with a list of statements. We used these results to provide guidance to other health care professionals on how best to image men with PCa and what treatments to give, when, and in what order, based on the information the images provide.</p

European Association of Nuclear Medicine Focus 5 : Consensus on Molecular Imaging and Theranostics in Prostate Cancer

Funding/Support and role of the sponsor: This research was funded by the EANM and supported by unrestricted grants from Advanced Accelerator Applications—a Novartis company, Monrol, Spectrum Dynamics Medical Ltd., Blue Earth Diagnostics, GE HealthCare, ITM Isotope Technologies Munich SE, Siemens Healthineers, and Telix Pharmaceuticals. These sponsors had no direct or indirect influence on the programme and content of the EANM Focus 5 meeting and the writing or content of this consensus statement. Acknowledgements: We would like to thank Evelyn Mansutti, Susanne Koebe, Andrea Csismazia, Jutta Peter, Petra Neubauer, Andreas Felser, and Henrik Silber (all from EANM) for project management. We also acknowledge all who participated in EANM Focus 5 meeting and especially the patients who participated in clinical and research projects, making it possible to inform expert opinion.Peer reviewe