Site-specific π-clamp-mediated radiosynthesis of Ga and F PET radiopharmaceuticals.

The π-clamp-mediated conjugation method, which enables site-specific modification of cysteine residues, is a promising strategy for developing well-defined radiolabelled biomolecules for positron emission tomography (PET) imaging. We have applied this method to site-specifically attach the macrocyclic chelators "NODA" and "NODAGA" to the somatostatin receptor 2-targeted peptide, octreotate. The resulting novel NODA-octreotate and NODAGA-octreotate compounds can be radiolabelled with either [F]AlF or [Ga]Ga respectively.

Receptor-Targeted Peptide Conjugates Based on Diphosphines Enable Preparation of Tc and Re Theranostic Agents for Prostate Cancer.

Benchtop Mo/Tc and W/Re generators enable economical production of molecular theranostic Tc and Re radiopharmaceuticals, provided that simple, kit-based chemistry exists to radiolabel targeting vectors with these radionuclides. We have previously described a diphosphine platform that efficiently incorporates Tc into receptor-targeted peptides. Here, we report its application to label a prostate-specific membrane antigen (PSMA)-targeted peptide with Tc and Re for diagnostic imaging and systemic radiotherapy of prostate cancer.

In Vivo Trafficking of the Anticancer Drug Tris(8-Quinolinolato) Gallium (III) (KP46) by Gallium-68/67 PET/SPECT Imaging.

KP46 (tris(hydroxyquinolinato)gallium(III)) is an experimental, orally administered anticancer drug. Its absorption, delivery to tumours, and mode of action are poorly understood. We aimed to gain insight into these issues using gallium-67 and gallium-68 as radiotracers with SPECT and PET imaging in mice.

Technetium Nitrido Complexes of Tetradentate Thiosemicarbazones: Kit-Based Radiolabeling, Characterization, and Evaluation.

Bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators have demonstrated utility in nuclear medicine. In particular, the Cu complexes have been extensively developed for hypoxia imaging and molecular imaging of peptide and protein markers of disease. However, the chemistry and application of bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators in combination with Tc, the most widely used radionuclide in nuclear medicine, is underexplored.

Site-Specific Ga Radiolabeling of Trastuzumab Fab via Methionine for ImmunoPET Imaging.

Bioconjugates of antibodies and their derivatives radiolabeled with β-emitting radionuclides can be utilized for diagnostic PET imaging. Site-specific attachment of radioactive cargo to antibody delivery vectors provides homogeneous, well-defined immunoconjugates. Recent studies have demonstrated the utility of oxaziridine chemistry for site-specific labeling of methionine residues.

Versatile Diphosphine Chelators for Radiolabeling Peptides with Tc and Cu.

We have developed a diphosphine (DP) platform for radiolabeling peptides with Tc and Cu for molecular SPECT and PET imaging, respectively. Two diphosphines, 2,3-bis(diphenylphosphino)maleic anhydride (DP) and 2,3-bis(di--tolylphosphino)maleic anhydride (DP), were each reacted with a Prostate Specific Membrane Antigen-targeted dipeptide (PSMAt) to yield the bioconjugates DP-PSMAt and DP-PSMAt, as well as an integrin-targeted cyclic peptide, RGD, to yield the bioconjugates DP-RGD and DP-RGD. Each of these DP-PSMAt conjugates formed geometric /-[MO(DP-PSMAt)] (M = Tc, Tc, Re; X = Ph, Tol) complexes when reacted with [MO] motifs.

Probing Unexpected Reactivity in Radiometal Chemistry: Indium-111-Mediated Hydrolysis of Hybrid Cyclen-Hydroxypyridinone Ligands.

Chelators based on hydroxypyridinones have utility in incorporating radioactive metal ions into diagnostic and therapeutic agents used in nuclear medicine. Over the course of our hydroxypyridinone studies, we have prepared two novel chelators, consisting of a cyclen (1,4,7,10-tetraazacyclododecane) ring bearing two pendant hydroxypyridinone groups, appended via methylene acetamide motifs at either the 1,4-positions () or 1,7-positions () of the cyclen ring. In radiolabeling reactions of or with the γ-emitting radioisotope, [In]In, we have observed radiometal-mediated hydrolysis of a single amide group of either or .

Diphosphine Bioconjugates via Pt(0)-Catalyzed Hydrophosphination. A Versatile Chelator Platform for Technetium-99m and Rhenium-188 Radiolabeling of Biomolecules.

The ability to append targeting biomolecules to chelators that efficiently coordinate to the diagnostic imaging radionuclide, Tc, and the therapeutic radionuclide, Re, can potentially enable receptor-targeted "theranostic" treatment of disease. Here we show that Pt(0)-catalyzed hydrophosphination reactions are well-suited to the derivatization of diphosphines with biomolecular moieties enabling the efficient synthesis of ligands of the type PhPCHCHP(CHCH-Glc) (, where Glc = a glucose moiety) using the readily accessible PhPCHCHPH and acryl derivatives. It is shown that hydrophosphination of an acrylate derivative of a deprotected glucose can be carried out in aqueous media.

An indium-111-labelled membrane-targeted peptide for cell tracking with radionuclide imaging.

Cell labelling agents that enable longitudinal tracking of administered cells will support the clinical development of cell-based therapies. Radionuclide imaging with gamma and positron-emitting radioisotopes can provide quantitative and longitudinal mapping of cells . To make this widely accessible and adaptable to a range of cell types, new, versatile and simple methods for directly radiolabelling cells are required.

Ultrathin, high-speed, all-optical photoacoustic endomicroscopy probe for guiding minimally invasive surgery.

Photoacoustic (PA) endoscopy has shown significant potential for clinical diagnosis and surgical guidance. Multimode fibres (MMFs) are becoming increasingly attractive for the development of miniature endoscopy probes owing to their ultrathin size, low cost and diffraction-limited spatial resolution enabled by wavefront shaping. However, current MMF-based PA endomicroscopy probes are either limited by a bulky ultrasound detector or a low imaging speed that hindered their usability.

Targeting integrin αvβ6 with gallium-68 tris (hydroxypyridinone) based PET probes.

Expression of the cellular transmembrane receptor αvβ6 integrin is mostly restricted to malignant epithelial cells in a wide variety of carcinomas, including pancreatic and others derived from epithelial tissues. Thus, this protein is considered an attractive target for tumour imaging and therapy. Two different Ga hexadentate tris (3,4-hydroxypyridinone) (THP) chelators were produced in this study and coupled to the αvβ6 integrin-selective peptide (FRGDLAFp(NMe)K) NHS chemistry.

Hexadentate technetium-99m bis(thiosemicarbazonato) complexes: synthesis, characterisation and biodistribution.

The syntheses of non-oxido/non-nitrido bis(thiosemicarbazonato)technetium(V) complexes featuring a series of alkyl and ether substituents is presented. The bis(thiosemicarbazones) were radiolabelled with technetium-99m using an optimised one-pot synthesis from [Tc][TcO]. Mass spectrometry and computational chemistry data suggested a distorted trigonal prismatic coordination environment for the bis(thiosemicarbazonato)technetium(V) complexes by way of a bis(thiosemicarbazone)technetium(V)-oxido intermediate complex.

Toward Bifunctional Chelators for Thallium-201 for Use in Nuclear Medicine.

Auger electron therapy exploits the cytotoxicity of low-energy electrons emitted during radioactive decay that travel very short distances (typically <1 μm). Tl, with a half-life of 73 h, emits ∼37 Auger and other secondary electrons per decay and can be tracked as its gamma emissions enable SPECT imaging. Despite the useful nuclear properties of Tl, satisfactory bifunctional chelators to incorporate it into bioconjugates for molecular targeting have not been developed.

To chelate thallium(I) - synthesis and evaluation of Kryptofix-based chelators for Tl.

While best known for its toxic properties, thallium has also been explored for applications in nuclear diagnostics and medicine. Indeed, [Tl]TlCl has been used extensively for nuclear imaging in the past before it was superceded by other radionuclides such as Tc. One reason for this loss of interest is the severe lack of suitable organic chelators able to effectively coordinate ionic forms of Tl and deliver it to specific diseased tissue by means of attached biological vectors.

N-Centered Tripodal Phosphine Re(V) and Tc(V) Oxo Complexes: Revisiting a [3 + 2] Mixed-Ligand Approach.

N-Triphos derivatives (NP, R = alkyl, aryl) and asymmetric variants (NPX, R' = alkyl, aryl, X = OH, NR, NRR') are an underexplored class of tuneable, tripodal ligands in relation to the coordination chemistry of Re and Tc for biomedical applications. Mixed-ligand approaches are a flexible synthetic route to obtain Tc complexes of differing core structures and physicochemical properties. Reaction of the NP ligand with the Re(V) oxo precursor [ReOCl(PPh)] generated the bidentate complex [ReOCl(κ-NPOH)], which possesses an unusual AA'BB'XX' spin system with a characteristic second-order NMR lineshape that is sensitive to the bi- or tridentate nature of the coordinating diphosphine unit.

A General Design Strategy Enabling the Synthesis of Hydrolysis-Resistant, Water-Stable Titanium(IV) Complexes.

Despite its prevalence in the environment, the chemistry of the Ti ion has long been relegated to organic solutions or hydrolyzed TiO polymorphs. A knowledge gap in stabilizing molecular Ti species in aqueous environments has prevented the use of this ion for various applications such as radioimaging, design of water-compatible metal-organic frameworks (MOFs), and aqueous-phase catalysis applications. Herein, we show a thorough thermodynamic screening of bidentate chelators with Ti in aqueous solution, as well as computational and structural analyses of key compounds.

Video-rate dual-modal photoacoustic and fluorescence imaging through a multimode fibre towards forward-viewing endomicroscopy.

Multimode fibres (MMFs) are becoming increasingly attractive in optical endoscopy as they promise to enable unparallelled miniaturisation, spatial resolution and cost. However, high-speed imaging with wavefront shaping has been challenging. Here, we report the development of a video-rate dual-modal photoacoustic (PA) and fluorescence microscopy probe with a high-speed digital micromirror device (DMD) towards forward-viewing endomicroscopy.

One-step, kit-based radiopharmaceuticals for molecular SPECT imaging: a versatile diphosphine chelator for Tc radiolabelling of peptides.

Radiotracers labelled with technetium-99m (Tc) enable accessible diagnostic imaging of disease, provided that radiotracer preparation is simple. Whilst Tc radiopharmaceuticals for imaging perfusion are routinely prepared from kits, and regularly used in healthcare, there are no Tc-labelled receptor-targeted radiopharmaceuticals in widespread clinical use. This is in part due to the multistep radiosyntheses required for the latter.

Oxorhenium(V) and Oxotechnetium(V) Complexes of NS Tetradentate Ligands with a Styrylpyridyl Functional Group: Toward Imaging Agents to Assist in the Diagnosis of Alzheimer's Disease.

Alzheimer's disease (AD) is associated with the presence of amyloid plaques in the brain mainly comprised of aggregated forms of amyloid-β (Aβ). Molecules radiolabeled with technetium-99m that cross the blood-brain barrier (BBB) and selectively bind to Aβ plaques have the potential to assist in the diagnosis of AD using single-photon emission computed tomography imaging. In this work, three new tetradentate ligands of pyridyl, amide, amine and thiol donors, featuring a styrylpyridyl group that is known to interact with amyloid plaques, were prepared.

An overview of nuclear medicine research in the UK and the landscape for clinical adoption.

Background And Objectives: Nuclear medicine contributes greatly to the clinical management of patients and experimental medicine. This report aims to (1) outline the current landscape of nuclear medicine research in the UK, including current facilities and recent or ongoing clinical studies and (2) provide information about the available pathways for clinical adoption and NHS funding (commissioning) of radiopharmaceuticals.

Methods: Evidence was obtained through database searches for UK-based nuclear medicine clinical studies and by conducting a questionnaire-based survey of UK radiopharmaceutical production facilities.

Validation of the plasmid study to relate DNA damaging effects of radionuclides to those from external beam radiotherapy.

Introduction: The biological consequences of absorbed radiation doses are ill-defined for radiopharmaceuticals, unlike for external beam radiotherapy (EBRT). A reliable assay that assesses the biological consequences of any radionuclide is much needed. Here, we evaluated the cell-free plasmid DNA assay to determine the relative biological effects of radionuclides such as Auger electron-emitting [Ga]GaCl or [In]InCl compared to EBRT.