Rigid Macrocycle Metal Complexes as CXCR4 Chemokine Receptor Antagonists: Influence of Ring Size.

Understanding the role of chemokine receptors in health and disease has been of increasing interest in recent years. Chemokine receptor CXCR4 has been extensively studied because of its defined role in immune cell trafficking, HIV infection, inflammatory diseases, and cancer progression. We have developed high affinity rigidified CXCR4 antagonists that incorporate metal ions to optimize the binding interactions with the aspartate side chains at the extracellular surface of the CXCR4 chemokine receptor and increase the residence time.

Combining Nuclear Medicine With Other Modalities: Future Prospect for Multimodality Imaging.

This meeting report summarizes a consultants meeting that was held at International Atomic Energy Agency Headquarters, Vienna, in July 2022 to provide an update on the development of multimodality imaging by combining nuclear medicine imaging agents with other nonradioactive molecular probes and/or biomedical imaging techniques.

Optimised production of technetium-94m for PET imaging by proton-irradiation of phosphomolybdic acid in cyclotron liquid target.

Natural-abundance phosphomolybdic acid (H(MoPO) ‧12HO, 0.181-0.552 g Mo/mL) solutions were irradiated with 12.

-IV restriction: a new configuration for metal bis-cyclam complexes as potent CXCR4 inhibitors.

The chemokine receptor CXCR4 is implicated in multiple diseases including inflammatory disorders, cancer growth and metastasis, and HIV/AIDS. CXCR4 targeting has been evaluated in treating cancer metastasis and therapy resistance. Cyclam derivatives, most notably AMD3100 (Plerixafor™), are a common motif in small molecule CXCR4 antagonists.

Automated sulfur-[F]fluoride exchange radiolabelling of a prostate specific membrane antigen (PSMA) targeted ligand using the GE FASTlab™ cassette-based platform.

Sulfur-[F]fluoride exchange radiochemistry is a rapid and convenient method for incorporating fluorine-18 into biologically active molecules. We report a fully automated radiolabelling procedure for the synthesis of a [F]SOF-bearing prostate specific membrane antigen (PSMA) targeted ligand ([F]5) using the GE FASTLab™ cassette-based platform in a 25.0 ± 2.

In vivo validation of Ga-labeled AMD3100 conjugates for PET imaging of CXCR4.

Introduction: The chemokine receptor CXCR4 has been shown to be over-expressed in multiple types of cancer and is usually associated with aggressive phenotypes and poor prognosis. Successfully targeting and imaging the expression level of this receptor in tumours could inform treatment selection and facilitate patient stratification.

Methods: Known conjugates of AMD3100 that are specific to CXCR4 have been radiolabelled with gallium-68 and evaluated in naïve and tumour-bearing mice.

, a Chelator for Ga Positron Emission Tomography: Hydroxide Coordination Increases Biological Stability of [Ga][Ga(BnDT3A)(OH)].

The chelator was used to produce a novel Ga complex for positron emission tomography (PET). Unusually, this system is stabilized by a coordinated hydroxide in aqueous solutions above pH 5, which confers sufficient stability for it to be used for PET. complexes Ga in a hexadentate manner, forming a complex with log ([Ga()]) = 18.

Epigenetic potentiation of somatostatin-2 by guadecitabine in neuroendocrine neoplasias as a novel method to allow delivery of peptide receptor radiotherapy.

Background: Somatostatin receptor-2 (SSTR2) is expressed on cell surface of neuroendocrine neoplasias; its presence is exploited for the delivery of peptide receptor radionuclide therapy (PRRT). Patients with no or low expression of SSTR2 are not candidates for PRRT. SSTR2 promotor undergoes epigenetic modification, known to regulate gene expression.

Spore exines increase vitamin D clinical bioavailability by mucoadhesion and bile triggered release.

Sporopollenin exine capsules (SpECs) are microcapsules derived from the outer shells (exines) of plant spore and pollen grains. This work reports the first clinical study on healthy volunteers to show enhanced bioavailability of vitamin D encapsulated in SpECs from Lycopodium clavatum L. spore grains vs vitamin D alone, and the first evidence (in vitro, ex vivo and in vivo) of mechanisms to account for the enhancement and release of the active in the small intestine.

The aluminium-[F]fluoride revolution: simple radiochemistry with a big impact for radiolabelled biomolecules.

The aluminium-[F]fluoride ([F]AlF) radiolabelling method combines the favourable decay characteristics of fluorine-18 with the convenience and familiarity of metal-based radiochemistry and has been used to parallel gallium-68 radiopharmaceutical developments. As such, the [F]AlF method is popular and widely implemented in the development of radiopharmaceuticals for the clinic. In this review, we capture the current status of [F]AlF-based technology and reflect upon its impact on nuclear medicine, as well as offering our perspective on what the future holds for this unique radiolabelling method.

Multivalency in CXCR4 chemokine receptor targeted iron oxide nanoparticles.

The CXCR4 chemokine receptor is an important biomolecular target in cancer diagnostics and therapeutics. In a new multivalent approach, iron oxide nanoparticles were conjugated with multiple binding units of a low affinity azamacrocylic CXCR4 antagonist. The silica coated nanostructure has good suspension stability, a mode size of 72 nm and high affinity for CXCR4, showing >98% inhibition of anti-CXCR4 mAb binding in a receptor binding competition assay on Jurkat cells.

PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma.

Objective: Neoadjuvant chemoradiotherapy (neo-CRT) prior to surgery is the standard of care for oesophageal adenocarcinoma (OAC) patients. Unfortunately, most patients fail to respond to treatment. MiR-187 was previously shown to be downregulated in neo-CRT non-responders, whist miR-187 overexpression enhanced radiosensitivity and upregulated .

Synthesis of a porphyrin with histidine-like chelate: an efficient path towards molecular PDT/SPECT theranostics.

The goal of "personalised" medicine has seen a growing interest in the development of theranostic agents. Bifunctional, and targeted-trifunctional, theranostic water-soluble porphyrins with a histidine-like chelating group have been synthesised via copper-catalysed azide-alkyne cycloaddition (CuAAC) "click" chemistry in high yield and purity. They are capable of photodynamic treatment and [99mTc(CO)3]+ complexation for single-photon emission computed tomography (SPECT) imaging, with a radiochemical yield of >95%.

Use of non-Gaussian time-of-flight kernels for image reconstruction of Monte Carlo simulated data of ultra-fast PET scanners.

Introduction: Time-of-flight (TOF) positron emission tomography (PET) scanners can provide significant benefits by improving the noise properties of reconstructed images. In order to achieve this, the timing response of the scanner needs to be modelled as part of the reconstruction process. This is currently achieved using Gaussian TOF kernels.

An ethylene cross-bridged pentaazamacrocycle and its Cu complex: constrained ligand topology and excellent kinetic stability.

Rigid and topologically constrained ethylene cross-bridged tetraazamacrocycles have been increasingly utilised for thirty years as they form remarkably stable transition metal complexes for catalysis, biomedical imaging, and inorganic drug molecule applications. Extending these benefits to pentaazamacrocycles has been achieved and a first transition metal complex prepared and structurally characterized.

On-chip electrochemical detection of glucose towards the miniaturised quality control of carbohydrate-based radiotracers.

The miniaturisation of positron emission tomography (PET) radiotracer production is facilitating a move towards a dose-on-demand strategy that would enable a stratified approach to patient diagnostics, but while the on-chip synthesis steps have been demonstrated, the subsequent quality control (QC) testing steps have received much less attention. As part of the development of an integrated QC platform for PET tracers, we have developed two microfluidic electrochemical detectors for the pulsed amperometric detection (PAD) of carbohydrate-based radiotracers, with a particular view to the QC testing of the most important tracer, [F]2-fluoro-2-deoxy-d-glucose ([F]FDG). The first device employed a commercial screen-printed electrode (SPE) to enable a single-use format, while the second device incorporated wire electrodes for use as a more permanent fixture in a QC instrument.

Water-Soluble Rhenium Phosphine Complexes Incorporating the PhC(X) Motif (X = O, NH): Structural and Cytotoxicity Studies.

Reaction of [ReOCl(PPh)] or [ReOI(PPh)] with 2,2'-diphenylglycine (dpgH) in refluxing ethanol afforded the air-stable complex [ReO(dpgH)(dpg)(PPh)] (). Treatment of [ReO(OEt)I(PPh)] with 1,2,3-triaza-7-phosphaadamantane (PTA) afforded the complex [ReO(OEt)I(PTA)] (). Reaction of [ReOI(PTA)] with dpgH led to the isolation of the complex [Re(NCPh)I(PTA)]·0.

Spill-in counts in the quantification of F-florbetapir on Aβ-negative subjects: the effect of including white matter in the reference region.

Background: We aim to provide a systematic study of the impact of white matter (WM) spill-in on the calculation of standardized uptake value ratios (SUVRs) on Aβ-negative subjects, and we study the effect of including WM in the reference region as a compensation. In addition, different partial volume correction (PVC) methods are applied and evaluated.

Methods: We evaluated magnetic resonance imaging and F-AV-45 positron emission tomography data from 122 cognitively normal (CN) patients recruited at the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Towards dual SPECT/optical bioimaging with a mitochondrial targeting, Tc(i) radiolabelled 1,8-naphthalimide conjugate.

A series of six different 1,8-naphthalimide conjugated dipicolylamine ligands (L1-6) have been synthesised and characterised. The ligands possess a range of different linker units between the napthalimide fluorophore and dipcolylamine chelator which allow the overall lipophilicity to be tuned. A corresponding series of Re(i) complexes have been synthesised of the form fac-[Re(CO)3(L1-6)]BF4.

Cell proliferation detected using [F]FLT PET/CT as an early marker of abdominal aortic aneurysm.

Background: Abdominal aortic aneurysm (AAA) is a focal aortic dilatation progressing towards rupture. Non-invasive AAA-associated cell proliferation biomarkers are not yet established. We investigated the feasibility of the cell proliferation radiotracer, fluorine-18-fluorothymidine ([F]FLT) with positron emission tomography/computed tomography (PET/CT) in a progressive pre-clinical AAA model (angiotensin II, AngII infusion).

MRI and PET/MRI in hematologic malignancies.

The role of MRI differs considerably between the three main groups of hematological malignancies: lymphoma, leukemia, and myeloma. In myeloma, whole-body MRI (WB-MRI) is recognized as a highly sensitive test for the assessment of myeloma, and is also endorsed by clinical guidelines, especially for detection and staging. In lymphoma, WB-MRI is presently not recommended, and merely serves as an alternative technique to the current standard imaging test, [ F]FDG-PET/CT, especially in pediatric patients.

Cu PET Imaging of the CXCR4 Chemokine Receptor Using a Cross-Bridged Cyclam Bis-Tetraazamacrocyclic Antagonist.

Expression of the chemokine receptor chemokine C-X-C motif receptor 4 (CXCR4) plays an important role in cancer metastasis, in autoimmune diseases, and during stem cell-based repair processes after stroke and myocardial infarction. Previously reported PET imaging agents targeting CXCR4 suffer from either high nonspecific uptake or bind only to the human form of the receptor. The objective of this study was to develop a high-stability Cu-labeled small-molecule PET agent for imaging both human and murine CXCR4 chemokine receptors.

Development of an anatomically correct mouse phantom for dosimetry measurement in small animal radiotherapy research.

Significant improvements in radiotherapy are likely to come from biological rather than technical optimization, for example increasing tumour radiosensitivity via combination with targeted therapies. Such paradigms must first be evaluated in preclinical models for efficacy, and recent advances in small animal radiotherapy research platforms allow advanced irradiation protocols, similar to those used clinically, to be carried out in orthotopic models. Dose assessment in such systems is complex however, and a lack of established tools and methodologies for traceable and accurate dosimetry is currently limiting the capabilities of such platforms and slowing the clinical uptake of new approaches.