Translation of the highly promising electrogenerated chemiluminescence (ECL) properties of Ir(
iii
) complexes (with tri-
n
-propylamine (TPrA) as a co-reactant) into a new generation of ECL labels ...for ligand binding assays necessitates the introduction of functionality suitable for bioconjugation. Modification of the ligands, however, can affect not only the photophysical and electrochemical properties of the complex, but also the reaction pathways available to generate light. Through a combined theoretical and experimental study, we reveal the limitations of conventional approaches to the design of electrochemiluminophores and introduce a new class of ECL label, Ir(C^N)
2
(pt-TOxT-Sq)
+
(where C^N is a range of possible cyclometalating ligands, and pt-TOxT-Sq is a pyridyltriazole ligand with trioxatridecane chain and squarate amide ethyl ester), which outperformed commercial Ir(
iii
) complex labels in two commonly used assay formats. Predicted limits on the redox potentials and emission wavelengths of Ir(
iii
) complexes capable of generating ECL
via
the dominant pathway applicable in microbead supported ECL assays were experimentally verified by measuring the ECL intensities of the parent luminophores at different applied potentials, and comparing the ECL responses for the corresponding labels under assay conditions. This study provides a framework to tailor ECL labels for specific assay conditions and a fundamental understanding of the ECL pathways that will underpin exploration of new luminophores and co-reactants.
A new strategy to create iridium(
iii
)-based ECL labels reveals limitations of conventional approaches.
The molecules known as bis(thiosemicarbazones) derived from 1,2-diones can act as tetradentate ligands for Cu(II), forming stable, neutral complexes. As a family, these complexes possess fascinating ...biological activity. This critical review presents an historical perspective of their progression from potential chemotherapeutics through to more recent applications in nuclear medicine. Methods of synthesis are presented followed by studies focusing on their potential application as anti-cancer agents and more recent investigations into their potential as therapeutics for Alzheimer's disease. The Cu(II) complexes are of sufficient stability to be used to coordinate copper radioisotopes for application in diagnostic and therapeutic radiopharmaceuticals. Detailed understanding of the coordination chemistry has allowed careful manipulation of the metal based properties to engineer specific biological activities. Perhaps the most promising complex radiolabelled with copper radioisotopes to date is Cu(II)(atsm), which has progressed to clinical trials in humans (162 references).
There are several isotopes of copper and rhenium that are of interest in the development of new molecular imaging or radiotherapeutic agents. This perspective article highlights the role of ...coordination chemistry in the design of copper and rhenium radiopharmaceuticals engineered to selectively target tissue of interest such as cancer cells or pathological features associated with Alzheimer's disease. The coordination chemistry of copper
bis
(thiosemicarbazone) derivatives and copper macrocyclic complexes is discussed in terms of their potential application as targeted positron emission tomography tracers for non-invasive diagnostic imaging. A range of rhenium complexes with different ligands with rhenium in different oxidation states are introduced and their potential to be translated to new radiotherapeutic agents discussed.
There are several isotopes of copper and rhenium that are of interest in the development of new molecular imaging or radiotherapeutic agents. This perspective article highlights the role of coordination chemistry in the design of copper and rhenium radiopharmaceuticals.
Alzheimer's disease is the most common form of age-related neurodegenerative dementia. The disease is characterised by the presence of plaques in the cerebral cortex. The major constituent of these ...plaques is aggregated amyloid-β peptide. This review focuses on the molecular aspects of metal complexes designed to bind to amyloid-β. The development of radioactive metal-based complexes of copper and technetium designed as diagnostic imaging agents to detect amyloid burden in the brain is discussed. Separate sections of the review discuss the use of luminescent metal complexes to act as non-conventional probes of amyloid formation and recent research into the use of metal complexes as inhibitors of amyloid formation and toxicity.
The use radioactive copper and technetium complexes as amyloid imaging agents, the use of luminescent metal complexes as non-conventional probes of amyloid formation and the potential of metal complexes to be inhibitors of amyloid toxicity are discussed.
Background and Purpose
Diacetyl‐bis(4‐methyl‐3‐thiosemicarbazonato)copperII (CuII(atsm)) ameliorates neurodegeneration and delays disease progression in mouse models of amyotrophic lateral sclerosis ...(ALS) and Parkinson's disease (PD), yet the mechanism of action remains uncertain. Promising results were recently reported for separate Phase 1 studies in ALS patients and PD patients. Affected tissue in these disorders shares features of elevated Fe, low glutathione and increased lipid peroxidation consistent with ferroptosis, a novel form of regulated cell death. We therefore evaluated the ability of CuII(atsm) to inhibit ferroptosis.
Experimental Approach
Ferroptosis was induced in neuronal cell models by inhibition of glutathione peroxidase‐4 activity with RSL3 or by blocking cystine uptake with erastin. Cell viability and lipid peroxidation were assessed and the efficacy of CuII(atsm) was compared to the known antiferroptotic compound liproxstatin‐1.
Key Results
CuII(atsm) protected against lipid peroxidation and ferroptotic lethality in primary and immortalised neuronal cell models (EC50: ≈130 nM, within an order of magnitude of liproxstatin‐1). NiII(atsm) also prevented ferroptosis with similar potency, whereas ionic CuII did not. In cell‐free systems, CuII(atsm) and NiII(atsm) inhibited FeII‐induced lipid peroxidation, consistent with these compounds quenching lipid radicals.
Conclusions and Implications
The antiferroptotic activity of CuII(atsm) could therefore be the disease‐modifying mechanism being tested in ALS and PD trials. With potency in vitro approaching that of liproxstatin‐1, CuII(atsm) possesses favourable properties such as oral bioavailability and entry into the brain that make it an attractive investigational product for clinical trials of ferroptosis‐related diseases.
Magnetic resonance spectroscopy is one of the most important tools in chemical and bio-medical research. However, sensitivity limitations typically restrict imaging resolution to ~ 10 µm. Here we ...bring quantum control to the detection of chemical systems to demonstrate high-resolution electron spin imaging using the quantum properties of an array of nitrogen-vacancy centres in diamond. Our electron paramagnetic resonance microscope selectively images electronic spin species by precisely tuning a magnetic field to bring the quantum probes into resonance with the external target spins. This provides diffraction limited spatial resolution of the target spin species over a field of view of 50 × 50 µm
with a spin sensitivity of 10
spins per voxel or ∼100 zmol. The ability to perform spectroscopy and dynamically monitor spin-dependent redox reactions at these scales enables the development of electron spin resonance and zepto-chemistry in the physical and life sciences.Electron paramagnetic resonance spectroscopy has important scientific and medical uses but improving the resolution of conventional methods requires cryogenic, vacuum environments. Simpson et al. show nitrogen vacancy centres can be used for sub-micronmetre imaging with improved sensitivity in ambient conditions.
Preliminary explorations of the annihilation electrogenerated chemiluminescence (ECL) of mixed metal complexes have revealed opportunities to enhance emission intensities and control the relative ...intensities from multiple luminophores through the applied potentials. However, the mechanisms of these systems are only poorly understood. Herein, we present a comprehensive characterisation of the annihilation ECL of mixtures of tris(2,2'-bipyridine)ruthenium(ii) hexafluorophosphate (Ru(bpy)
(PF
)
) and
-tris(2-phenylpyridine)iridium(iii) (Ir(ppy)
). This includes a detailed investigation of the change in emission intensity from each luminophore as a function of both the applied electrochemical potentials and the relative concentrations of the two complexes, and a direct comparison with two mixed (Ru/Ir) ECL systems for which emission from only the ruthenium-complex was previously reported. Concomitant emission from both luminophores was observed in all three systems, but only when: (1) the applied potentials were sufficient to generate the intermediates required to form the electronically excited state of both complexes; and (2) the concentration of the iridium complex (relative to the ruthenium complex) was sufficient to overcome quenching processes. Both enhancement and quenching of the ECL of the ruthenium complex was observed, depending on the experimental conditions. The observations were rationalised through several complementary mechanisms, including resonance energy transfer and various energetically favourable electron-transfer pathways.
Compared to tris(2‐phenylpyridine)iridium(III) (Ir(ppy)3), iridium(III) complexes containing difluorophenylpyridine (df‐ppy) and/or an ancillary triazolylpyridine ligand ...3‐phenyl‐1,2,4‐triazol‐5‐ylpyridinato (ptp) or 1‐benzyl‐1,2,3‐triazol‐4‐ylpyridine (ptb) exhibit considerable hypsochromic shifts (ca. 25–60 nm), due to the significant stabilising effect of these ligands on the HOMO energy, whilst having relatively little effect on the LUMO. Despite their lower photoluminescence quantum yields compared with Ir(ppy)3 and Ir(df‐ppy)3, the iridium(III) complexes containing triazolylpyridine ligands gave greater electrogenerated chemiluminescence (ECL) intensities (using tri‐n‐propylamine (TPA) as a co‐reactant), which can in part be ascribed to the more energetically favourable reactions of the oxidised complex (M+) with both TPA and its neutral radical oxidation product. The calculated iridium(III) complex LUMO energies were shown to be a good predictor of the corresponding M+ LUMO energies, and both HOMO and LUMO levels are related to ECL efficiency. The theoretical and experimental data together show that the best strategy for the design of efficient new blue‐shifted electrochemiluminophores is to aim to stabilise the HOMO, while only moderately stabilising the LUMO, thereby increasing the energy gap but ensuring favourable thermodynamics and kinetics for the ECL reaction. Of the iridium(III) complexes examined, Ir(df‐ppy)2(ptb)+ was most attractive as a blue‐emitter for ECL detection, featuring a large hypsochromic shift (λmax=454 and 484 nm), superior co‐reactant ECL intensity than the archetypal homoleptic green and blue emitters: Ir(ppy)3 and Ir(df‐ppy)3 (by over 16‐fold and threefold, respectively), and greater solubility in polar solvents.
Into the blue: Theoretical and experimental studies reveal the most effective strategies for the design of blue‐shifted iridium(III) complexes for efficient electrogenerated chemiluminescence. Stabilisation of the HOMO while only moderately stabilising the LUMO increases the energy gap, thus ensuring favourable thermodynamics and kinetics for the reaction leading to the excited state (see figure).
Molecular changes in malignant tissue can lead to an increase in the expression levels of various proteins or receptors that can be used to target the disease. In oncology, diagnostic imaging and ...radiotherapy of tumors is possible by attaching an appropriate radionuclide to molecules that selectively bind to these target proteins. The term "theranostics" describes the use of a diagnostic tool to predict the efficacy of a therapeutic option. Molecules radiolabeled with γ-emitting or β
-emitting radionuclides can be used for diagnostic imaging using single photon emission computed tomography or positron emission tomography. Radionuclide therapy of disease sites is possible with either α-, β-, or Auger-emitting radionuclides that induce irreversible damage to DNA. This Focus Review centers on the chemistry of theranostic approaches using metal radionuclides for imaging and therapy. The use of tracers that contain β
-emitting gallium-68 and β-emitting lutetium-177 will be discussed in the context of agents in clinical use for the diagnostic imaging and therapy of neuroendocrine tumors and prostate cancer. A particular emphasis is then placed on the chemistry involved in the development of theranostic approaches that use copper-64 for imaging and copper-67 for therapy with functionalized sarcophagine cage amine ligands. Targeted therapy with radionuclides that emit α particles has potential to be of particular use in late-stage disease where there are limited options, and the role of actinium-225 and lead-212 in this area is also discussed. Finally, we highlight the challenges that impede further adoption of radiotheranostic concepts while highlighting exciting opportunities and prospects.
Conspectus Molecular imaging with antibodies radiolabeled with positron-emitting radionuclides combines the affinity and selectivity of antibodies with the sensitivity of Positron Emission Tomography ...(PET). PET imaging allows the visualization and quantification of the biodistribution of the injected radiolabeled antibody, which can be used to characterize specific biological interactions in individual patients. This characterization can provide information about the engagement of the antibody with a molecular target such as receptors present in elevated levels in tumors as well as providing insight into the distribution and clearance of the antibody. Potential applications of clinical PET with radiolabeled antibodies include identifying patients for targeted therapies, characterization of heterogeneous disease, and monitoring treatment response. Antibodies often take several days to clear from the blood pool and localize in tumors, so PET imaging with radiolabeled antibodies requires the use of a radionuclide with a similar radioactive half-life. Zirconium-89 is a positron-emitting radionuclide that has a radioactive half-life of 78 h and relatively low positron emission energy that is well suited to radiolabeling antibodies. It is essential that the zirconium-89 radionuclide be attached to the antibody through chemistry that provides an agent that is stable in vivo with respect to the dissociation of the radionuclide without compromising the biological activity of the antibody. This Account focuses on our research using a simple derivative of the bacterial siderophore desferrioxamine (DFO) with a squaramide ester functional group, DFO-squaramide (DFOSq), to link the chelator to antibodies. In our work, we produce conjugates with an average ∼4 chelators per antibody, and this does not compromise the binding of the antibody to the target. The resulting antibody conjugates of DFOSq are stable and can be easily radiolabeled with zirconium-89 in high radiochemical yields and purity. Automated methods for the radiolabeling of DFOSq–antibody conjugates have been developed to support multicenter clinical trials. Evaluation of several DFOSq conjugates with antibodies and low molecular weight targeting agents in tumor mouse models gave PET images with high tumor uptake and low background. The promising preclinical results supported the translation of this chemistry to human clinical trials using two different radiolabeled antibodies. The potential clinical impact of these ongoing clinical trials is discussed. The use of DFOSq to radiolabel relatively low molecular weight targeting molecules, peptides, and peptide mimetics is also presented. Low molecular weight molecules typically clear the blood pool and accumulate in target tissue more rapidly than antibodies, so they are usually radiolabeled with positron-emitting radionuclides with shorter radioactive half-lives such as fluorine-18 (t 1/2 ∼ 110 min) or gallium-68 (t 1/2 ∼ 68 min). Radiolabeling peptides and peptide mimetics with zirconium-89, with its longer radioactive half-life (t 1/2 = 78 h), could facilitate the centralized manufacture and distribution of radiolabeled tracers. In addition, the ability to image patients at later time points with zirconium-89 based agents (e.g. 4–24 h after injection) may also allow the delineation of small or low-uptake disease sites as the delayed imaging results in increased clearance of the tracer from nontarget tissue and lower background signal.
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