Biodistribution and dosimetry of the PET radioligand [F]CHDI-650 in mice for detection of mutant huntingtin aggregates.

Background: Huntington's disease (HD) is a rare neurodegenerative disorder caused by an expansion of the CAG trinucleotide repeat in the huntingtin gene which encodes the mutant huntingtin protein (mHTT) that is associated with HD-related neuropathophysiology. Noninvasive visualization of mHTT aggregates in the brain, with positron emission tomography (PET), will allow to reliably evaluate the efficacy of therapeutic interventions in HD. This study aimed to assess the radiation burden of [F]CHDI-650, a novel fluorinated mHTT radioligand, in humans based on both in vivo and ex vivo biodistribution in mice and subsequent determination of dosimetry for dosing in humans.

Preclinical validation and kinetic modelling of the SV2A PET ligand [F]UCB-J in mice.

Synaptic vesicle protein 2A (SV2A) is ubiquitously expressed in presynaptic terminals where it functions as a neurotransmission regulator protein. Synaptopathy has been reported during healthy ageing and in a variety of neurodegenerative diseases. Positron emission tomography (PET) imaging of SV2A can be used to evaluate synaptic density.

Astatine-211 radiolabelling chemistry: from basics to advanced biological applications.

Background: At-radiopharmaceuticals are currently the subject of growing studies for targeted alpha therapy of cancers, which leads to the widening of the scope of the targeting vectors, from small molecules to peptides and proteins. This has prompted, during the past decade, to a renewed interest in developing novel At-labelling approaches and novel prosthetic groups to address the diverse scenarios and to reach improved efficiency and robustness of procedures as well as an appropriate in vivo stability of the label.

Main Body: Translated from the well-known (radio)iodine chemistry, the long preferred electrophilic astatodemetallation using trialkylaryltin precursors is now complemented by new approaches using electrophilic or nucleophilic At.

Development of caspase-3-selective activity-based probes for PET imaging of apoptosis.

Background: The cysteine-aspartic acid protease caspase-3 is recognized as the main executioner of apoptosis in cells responding to specific extrinsic and intrinsic stimuli. Caspase-3 represents an interesting biomarker to evaluate treatment response, as many cancer therapies exert their effect by inducing tumour cell death. Previously developed caspase-3 PET tracers were unable to reach routine clinical use due to low tumour uptake or lack of target selectivity, which are two important requirements for effective treatment response evaluation in cancer patients.

Optimizing SUV Analysis: A Multicenter Study on Preclinical FDG-PET/CT Highlights the Impact of Standardization.

Purpose: Preclinical imaging, with translational potential, lacks a standardized method for defining volumes of interest (VOIs), impacting data reproducibility. The aim of this study was to determine the interobserver variability of VOI sizes and standard uptake values (SUV and SUV) of different organs using the same [F]FDG-PET and PET/CT datasets analyzed by multiple observers. In addition, the effect of a standardized analysis approach was evaluated.

Trans-cyclooctene-a Swiss army knife for bioorthogonal chemistry: exploring the synthesis, reactivity, and applications in biomedical breakthroughs.

Background: Trans-cyclooctenes (TCOs) are highly strained alkenes with remarkable reactivity towards tetrazines (Tzs) in inverse electron-demand Diels-Alder reactions. Since their discovery as bioorthogonal reaction partners, novel TCO derivatives have been developed to improve their reactivity, stability, and hydrophilicity, thus expanding their utility in diverse applications.

Main Body: TCOs have garnered significant interest for their applications in biomedical settings.

Druglike, F-labeled PET Tracers Targeting Fibroblast Activation Protein.

Fibroblast activation protein (FAP) is a very reliable biomarker for tissue remodeling. FAP has so far mainly been studied in oncology, but there is growing interest in the enzyme in other diseases like fibrosis. Recently, FAP-targeting diagnostics and therapeutics have emerged, of which the so-called FAPIs are among the most promising representatives.

Next generation fibroblast activation protein (FAP) targeting PET tracers - The tetrazine ligation allows an easy and convenient way to F-labeled (4-quinolinoyl)glycyl-2-cyanopyrrolidines.

Small-molecular fibroblast activation protein inhibitor (FAPI)-based tracer have been shown to be promising Positron Emission Tomography (PET) Ga-labeled radiopharmaceuticals to image a variety of tumors including pancreatic, breast, and colorectal cancers, among others. In this study, we developed a novel F-labeled FAPI derivative. [F]6 was labeled using a synthon approach based on the tetrazine ligation.

Characterization of Structurally Diverse F-Labeled d-TCO Derivatives as a PET Probe for Bioorthogonal Pretargeted Imaging.

The pretargeted imaging strategy using inverse electron demand Diels-Alder (IEDDA) cycloaddition between a -cyclooctene (TCO) and tetrazine (Tz) has emerged and rapidly grown as a promising concept to improve radionuclide imaging and therapy in oncology. This strategy has mostly relied on the use of radiolabeled Tz together with TCO-modified targeting vectors leading to a rapid growth of the number of available radiolabeled tetrazines, while only a few radiolabeled TCOs are currently reported. Here, we aim to develop novel and structurally diverse F-labeled cis-dioxolane-fused TCO (d-TCO) derivatives to further expand the bioorthogonal toolbox for ligation and evaluate their potential for positron emission tomography (PET) pretargeted imaging.

First-in-human study of a novel cell death tracer [Tc]Tc-Duramycin: safety, biodistribution and radiation dosimetry in healthy volunteers.

Background: Imaging of cell death can provide an early indication of treatment response in cancer. [Tc]Tc-Duramycin is a small-peptide SPECT tracer that recognizes both apoptotic and necrotic cells by binding to phosphatidylethanolamine present in the cell membrane. Preclinically, this tracer has shown to have favorable pharmacokinetics and selective tumor accumulation early after the onset of anticancer therapy.

Site-specific Ga-labeled nanobody for PET imaging of CD70 expression in preclinical tumor models.

Background: CD70-CD27 is a costimulatory ligand-receptor pair in the tumor necrosis factor receptor family. With only limited expression in normal tissues, CD70 is constitutively expressed in a variety of solid tumors and hematologic malignancies, facilitating immunosuppression through CD27 signaling in the tumor microenvironment by enhanced survival of regulatory T cells, induction of T cell apoptosis, and T cell exhaustion. Consequently, CD70 is an increasingly recognized target for developing antibody-based therapies, but its expression patterns vary among different tumor types in spatial distribution, magnitude of expression and percentage of positive cells.

Improved Characteristics of RANKL Immuno-PET Imaging Using Radiolabeled Antibody Fab Fragments.

Purpose: RANKL expression in the tumor microenvironment has been identified as a biomarker of immune suppression, negating the effect of some cancer immunotherapies. Previously we had developed a radiotracer based on the FDA-approved RANKL-specific antibody denosumab, [Zr]Zr-DFO-denosumab, enabling successful immuno-PET imaging. Radiolabeled denosumab, however, showed long blood circulation and delayed tumor uptake, potentially limiting its applications.

Radionuclide Imaging of Cytotoxic Immune Cell Responses to Anti-Cancer Immunotherapy.

Cancer immunotherapy is an evolving and promising cancer treatment that takes advantage of the body's immune system to yield effective tumor elimination. Importantly, immunotherapy has changed the treatment landscape for many cancers, resulting in remarkable tumor responses and improvements in patient survival. However, despite impressive tumor effects and extended patient survival, only a small proportion of patients respond, and others can develop immune-related adverse events associated with these therapies, which are associated with considerable costs.

Positron emission tomography-magnetic resonance imaging as a research tool in musculoskeletal conditions.

Compared to positron emission tomography/computed tomography (PET/CT), the uptake of PET- magnetic resonance imaging (MRI) has been slow, even more so in clinical practice compared to the (pre-)clinical research setting. However, for applications in musculoskeletal (MSK) research, the combination of PET and MRI into a single modality offers attractive advantages over other imaging modalities. Most importantly, MRI has exquisite soft-tissue detail without the use of contrast agents or ionizing radiation, superior bone marrow visualization, and an extensive spectrum of distinct multiparametric assessment methods.

Immuno-PET Molecular Imaging of RANKL in Cancer.

Purpose: The involvement of RANK/RANKL signaling in the tumor microenvironment (TME) in driving response or resistance to immunotherapy has only very recently been recognized. Current quantification methods of RANKL expression suffer from issues such as sensitivity, variability, and uncertainty on the spatial heterogeneity within the TME, resulting in conflicting reports on its reliability and limited use in clinical practice. Non-invasive molecular imaging using immuno-PET is a promising approach combining superior targeting specificity of monoclonal antibodies (mAb) and spatial, temporal and functional information of PET.

Molecular Imaging of Apoptosis: The Case of Caspase-3 Radiotracers.

The molecular imaging of apoptosis remains an important method for the diagnosis and monitoring of the progression of certain diseases and the evaluation of the efficacy of anticancer apoptosis-inducing therapies. Among the multiple biomarkers involved in apoptosis, activated caspase-3 is an attractive target, as it is the most abundant of the executioner caspases. Nuclear imaging is a good candidate, as it combines a high depth of tissue penetration and high sensitivity, features necessary to detect small changes in levels of apoptosis.

Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA chelators.

Background: Fibroblast activation protein (FAP) is a proline selective serine protease that is overexpressed in tumor stroma and in lesions of many other diseases that are characterized by tissue remodeling. In 2014, a most potent FAP-inhibitor (referred to as UAMC1110) with low nanomolar FAP-affinity and high selectivity toward related enzymes such as prolyl oligopeptidase (PREP) and the dipeptidyl-peptidases (DPPs): DPP4, DPP8/9 and DPP2 were developed. This inhibitor has been adopted recently by other groups to create radiopharmaceuticals by coupling bifunctional chelator-linker systems.

Development of Antibody Immuno-PET/SPECT Radiopharmaceuticals for Imaging of Oncological Disorders-An Update.

Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are molecular imaging strategies that typically use radioactively labeled ligands to selectively visualize molecular targets. The nanomolar sensitivity of PET and SPECT combined with the high specificity and affinity of monoclonal antibodies have shown great potential in oncology imaging. Over the past decades a wide range of radio-isotopes have been developed into immuno-SPECT/PET imaging agents, made possible by novel conjugation strategies (e.

SPECT/CT: Standing on the Shoulders of Giants, It Is Time to Reach for the Sky!

Twenty years ago, SPECT/CT became commercially available, combining the strengths of both techniques: the diagnostic sensitivity of SPECT and the anatomic detail of CT. Other benefits initially included attenuation correction of SPECT reconstructions, ultimately evolving to correction techniques that would enable absolute tracer uptake quantification. Recent developments in SPECT hardware include solid-state digital systems with higher sensitivity and resolution, using novel collimator designs based on tungsten.

Preclinical Evaluation of a Novel F-Labeled dTCO-Amide Derivative for Bioorthogonal Pretargeted Positron Emission Tomography Imaging.

Pretargeted positron emission tomography (PET) imaging based on the bioorthogonal inverse-electron-demand Diels-Alder reaction between tetrazines (Tz) and -cyclooctenes (TCO) has emerged as a promising tool for solid tumor imaging, allowing the use of short-lived radionuclides in immune-PET applications. With this strategy, it became possible to achieve desirable target-to-background ratios and at the same time to decrease the radiation burden to nontargeted tissues because of the fast clearance of small PET probes. Here, we show the synthesis of novel F-labeled dTCO-amide probes for pretargeted immuno-PET imaging.

Improved stability of a novel fluorine-18 labeled TCO analogue for pretargeted PET imaging.

Introduction: Biorthogonal pretargeted imaging using the inverse electron demand Diels Alder (IEDDA) reaction between tetrazine (Tz) and trans-cyclooctene (TCO) is one of the most attractive strategies in molecular imaging. It allows the use of short-lived radioisotopes such as fluorine-18 for imaging of long circulating vectors with improved imaging contrast and reduced radiation dose. Here we aim to develop a novel F-labeled trans-cyclooctene (TCO) with improved metabolic stability and assess its potential usefulness in a pretargeted PET imaging approach.

Bone metastases in the era of targeted treatments: insights from molecular biology.

Bone metastases remain a common feature of advanced cancers and are associated with significant morbidity and mortality. Recent research has identified promising novel treatment targets to improve current treatment strategies for bone metastatic disease. This review summarizes the well-known and recently discovered molecular biology pathways in bone that govern normal physiological remodeling or drive the pathophysiological changes observed when bone metastases are present.

Caspase-3 probes for PET imaging of apoptotic tumor response to anticancer therapy.

Apoptosis is a highly regulated process involved in the normal organism development and homeostasis. In the context of anticancer therapy, apoptosis is also studied intensively in an attempt to induce cell death in cancer cells. Caspase activation is a known key event in the apoptotic process.

[Tc]duramycin for cell death imaging: Impact of kit formulation, purification and species difference.

Introduction: [Tc]duramycin is a SPECT tracer for cell death imaging. We evaluated the impact of kit formulation, purification and species difference on the pharmacokinetic profile and cell death targeting properties of [Tc]duramycin in order to define the optimal conditions for (pre-)clinical use.

Methods: Three kits were prepared (A: traditional formulation, B: containing 1/3 of ingredients, C: containing HYNIC-PEG-duramycin).

Treatment with A receptor antagonist KW6002 and caffeine intake regulate microglia reactivity and protect retina against transient ischemic damage.

Transient retinal ischemia is a major complication of retinal degenerative diseases and contributes to visual impairment and blindness. Evidences indicate that microglia-mediated neuroinflammation has a key role in the neurodegenerative process, prompting the hypothesis that the control of microglia reactivity may afford neuroprotection to the retina against the damage induced by ischemia-reperfusion (I-R). The available therapeutic strategies for retinal degenerative diseases have limited potential, but the blockade of adenosine A receptor (AR) emerges as candidate strategy.