Intranasal delivery of imaging agents to the brain.

The potential of intranasal administered imaging agents to altogether bypass the blood-brain barrier offers a promising non-invasive approach for delivery directly to the brain. This review provides a comprehensive analysis of the advancements and challenges of delivering neuroimaging agents to the brain by way of the intranasal route, focusing on the various imaging modalities and their applications in central nervous system diagnostics and therapeutics. The various imaging modalities provide distinct insights into the pharmacokinetics, biodistribution, and specific interactions of imaging agents within the brain, facilitated by the use of tailored tracers and contrast agents.

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.

Pre-targeting amyloid-β with antibodies for potential molecular imaging of Alzheimer's disease.

With the aim of developing the concept of pretargeted click chemistry for the diagnosis of Alzheimer's disease two antibodies specific for amyloid-β were modified to incorporate -cyclooctene functional groups. Two bis(thiosemicarbazone) compounds with pendant 1,2,4,5-tetrazine functional groups were prepared and radiolabelled with positron emitting copper-64. The new copper-64 complexes rapidly react with the -cyclooctene functionalized antibodies in a bioorthogonal click reaction and cross the blood-brain barrier in mice.

Modern Developments in Bifunctional Chelator Design for Gallium Radiopharmaceuticals.

The positron-emitting radionuclide gallium-68 has become increasingly utilised in both preclinical and clinical settings with positron emission tomography (PET). The synthesis of radiochemically pure gallium-68 radiopharmaceuticals relies on careful consideration of the coordination chemistry. The short half-life of 68 min necessitates rapid quantitative radiolabelling (≤10 min).

A Biodistribution Study of the Radiolabeled Kv1.3-Blocking Peptide DOTA-HsTX1[R14A] Demonstrates Brain Uptake in a Mouse Model of Neuroinflammation.

The voltage-gated potassium channel Kv1.3 regulates the pro-inflammatory function of microglia and is highly expressed in the post-mortem brains of individuals with Alzheimer's and Parkinson's diseases. HsTX1[R14A] is a selective and potent peptide inhibitor of the Kv1.

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.

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.

The Synthesis of a Bis(thiosemicarbazone) Macrocyclic Ligand and the Mn(II), Co(II), Zn(II) and Ga(III) Complexes.

A 1,4,7,10-tetraazacyclododecane (cyclen) variant bearing two thiosemicarbazone pendant groups has been prepared. The ligand forms complexes with Mn, Co and Zn. X-ray crystallography of the Mn, Co and Zn complexes showed that the ligand provides a six-coordinate environment for the metal ions.

An octadentate bis(semicarbazone) macrocycle: a potential chelator for lead and bismuth radiopharmaceuticals.

A variant of 1,4,7,10-tetraazacyclododecane (cyclen) bearing two semicarbazone pendant groups has been prepared. The octadentate ligand forms complexes with Bi3+ and Pb2+. X-ray crystallography showed that the neutral ligand provides an eight-coordinate environment for both metal ions and intermolecular hydrogen bond interactions have influenced the coordination environments of both complexes in the solid state.

Modification of Biodistribution and Brain Uptake of Copper Bis(thiosemicarbazonato) Complexes by the Incorporation of Amine and Polyamine Functional Groups.

The synthesis of new bis(thiosemicarbazonato)copper(II) complexes featuring polyamine substituents via selective transamination reactions is presented. Polyamines of different lengths, with different ionizable substituent groups, were used to modify and adjust the hydrophilic/lipophilic balance of the copper complexes. The new analogues were radiolabeled with copper-64 and their lipophilicities estimated using distribution coefficients.

Modulating Targeting of Poly(ethylene glycol) Particles to Tumor Cells Using Bispecific Antibodies.

Low-fouling or "stealth" particles composed of poly(ethylene glycol) (PEG) display a striking ability to evade phagocytic cell uptake. However, functionalizing them for specific targeting is challenging. To address this challenge, stealth PEG particles prepared by a mesoporous silica templating method are functionalized with bispecific antibodies (BsAbs) to obtain PEG-BsAb particles via a one-step binding strategy for cell and tumor targeting.

Tuning the properties of tris(hydroxypyridinone) ligands: efficient Ga chelators for PET imaging.

The prototype tris(1,6-dimethyl-3-hydroxypyridin-4-one) chelator for gallium-68, THPMe, has shown great promise for rapid and efficient kit-based 68Ga labelling of PET radiopharmaceuticals. Peptide derivatives of THPMe have been used to image expression of their target receptors in vivo in preclinical and clinical studies. Herein we describe new synthetic routes to the THP platform including replacing the 1,6-dimethyl-3-hydroxypyridin-4-one N1-CH3 group of THPMe with O (tris(6-methyl-3-hydroxypyran-4-one, THPO) and N1-H (tris(6-methyl-3-hydroxypyridin-4-one), THPH) groups.

Cu-SARTATE PET Imaging of Patients with Neuroendocrine Tumors Demonstrates High Tumor Uptake and Retention, Potentially Allowing Prospective Dosimetry for Peptide Receptor Radionuclide Therapy.

Imaging of somatostatin receptor expression is an established technique for staging of neuroendocrine neoplasia and determining the suitability of patients for peptide receptor radionuclide therapy. PET/CT using Ga-labeled somatostatin analogs is superior to earlier agents, but the rapid physical decay of the radionuclide poses logistic and regulatory challenges. Cu has attractive physical characteristics for imaging and provides a diagnostic partner for the therapeutic radionuclide Cu.

Comparison of macrocyclic and acyclic chelators for gallium-68 radiolabelling.

Gallium-68 (Ga) is a positron-emitting isotope used for clinical PET imaging of peptide receptor expression. Ga radiopharmaceuticals used in molecular PET imaging consist of disease-targeting biomolecules tethered to chelators that complex Ga. Ideally, the chelator will rapidly, quantitatively and stably coordinate Ga at room temperature, near neutral pH and low chelator concentration, allowing for simple routine radiopharmaceutical formulation.

Guest-induced Assembly of Bis(thiosemicarbazonato) Zinc(II) Coordination Nanotubes.

A Zn complex of the dianionic tetradentate ligand formed by deprotonation of glyoxal-bis(4-phenyl-3-thiosemicarbazone) (H gtsp) is a [3+3] trinuclear triangular prism. Recrystallization of this complex in the presence of either CO , CS , or CH CN leads to the formation of [4+4] open-ended charge-neutral tetranuclear coordination nanotubes, approximately 2 nm in length and with internal dimensions large enough to accommodate linear guest molecules, which serve to template their formation. Upon removal of the templating molecules the nanotubes demonstrated reversible sorption of CO with an isosteric enthalpy of sorption of 28 kJ mol at low loading.

Highly Sensitive Detection of Minimal Cardiac Ischemia using Positron Emission Tomography Imaging of Activated Platelets.

A reliable method for the diagnosis of minimal cardiac ischemia would meet a strong demand for the sensitive diagnosis of coronary artery disease in cardiac stress testing and risk stratification in patients with chest pain but unremarkable ECGs and biomarkers. We hypothesized that platelets accumulate early on in ischemic myocardium and a newly developed technology of non-invasive molecular PET imaging of activated platelets can thus detect minimal degrees of myocardial ischemia. To induce different degrees of minimal cardiac ischemia, the left anterior descending artery (LAD) was ligated for 10, 20 or 60 min.

Copper-64 Labeled Macrobicyclic Sarcophagine Coupled to a GRP Receptor Antagonist Shows Great Promise for PET Imaging of Prostate Cancer.

The gastrin-releasing peptide receptor (GRPr) is an important molecular target for the visualization and therapy of tumors and can be targeted with radiolabeled bombesin derivatives. The present study aims to develop statine-based bombesin receptor antagonists suitable for labeling with 64Cu for imaging by positron emission tomography (PET). The potent GRPr antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 was conjugated to the sarcophagine (3,6,10,13,16,19-hexaazabicyclo[6.

A versatile approach for the site-specific modification of recombinant antibodies using a combination of enzyme-mediated bioconjugation and click chemistry.

A unique two-step modular system for site-specific antibody modification and conjugation is reported. The first step of this approach uses enzymatic bioconjugation with the transpeptidase Sortase A for incorporation of strained cyclooctyne functional groups. The second step of this modular approach involves the azide-alkyne cycloaddition click reaction.

The ionic charge of copper-64 complexes conjugated to an engineered antibody affects biodistribution.

The development of biomolecules as imaging probes requires radiolabeling methods that do not significantly influence their biodistribution. Sarcophagine (Sar) chelators form extremely stable complexes with copper and are therefore a promising option for labeling proteins with (64)Cu. However, initial studies using the first-generation sarcophagine bifunctional chelator SarAr to label the engineered antibody fragment ch14.

Engineering poly(ethylene glycol) particles for improved biodistribution.

We report the engineering of poly(ethylene glycol) (PEG) hydrogel particles using a mesoporous silica (MS) templating method via tuning the PEG molecular weight, particle size, and the presence or absence of the template and investigate the cell association and biodistribution of these particles. An ex vivo assay based on human whole blood that is more sensitive and relevant than traditional cell-line based assays for predicting in vivo circulation behavior is introduced. The association of MS@PEG particles (template present) with granulocytes and monocytes is higher compared with PEG particles (template absent).

Bifunctional (64)Cu-labelled macrobicyclic cage amine isothiocyanates for immuno-positron emission tomography.

New macrobicyclic cage amine or "sarcophagine" (sar) bifunctional chelators have been synthesised that form copper complexes of exceptional in vivo stability and incorporate isothiocyanate (-NCS) functional groups for conjugation to an antibody. The chelators were synthesised from the methyl-capped complex [Mg(II)(CH3)(NH2)sar](2+). Coordination of Mg(II) within the cavity of the cage amine ligand protects the secondary amine atoms from reacting with the -NCS functional groups.

Tripodal tris(hydroxypyridinone) ligands for immunoconjugate PET imaging with (89)Zr(4+): comparison with desferrioxamine-B.

Due to its long half-life (78 h) and decay properties (77% electron capture, 23% β(+), Emax = 897 keV, Eav = 397 keV, Eγ = 909 keV, Iγ = 100%) (89)Zr is an appealing radionuclide for immunoPET imaging with whole IgG antibodies. Derivatives of the siderophore desferrioxamine-B (H3DFO) are the most widely used bifunctional chelators for coordination of (89)Zr(4+) because the radiolabeling of the resulting immunoconjugates is rapid under mild conditions. (89)Zr-DFO complexes are reportedly stable in vitro but there is evidence that (89)Zr(4+) is released in vivo, and subsequently taken up by the skeleton.

Single-chain antibody conjugated to a cage amine chelator and labeled with positron-emitting copper-64 for diagnostic imaging of activated platelets.

Imaging of activated platelets using an activation specific anti-GPIIb/IIIa integrin single-chain antibody (scFvanti-LIBS) conjugated to a positron emitting copper-64 complex of a cage amine sarcophagine chelator (MeCOSar) is reported. This tracer was compared in vitro to a (64)Cu(II) complex of the scFv conjugated to another commonly used macrocycle, DOTA. The scFvanti-LIBS-MeCOSar conjugate was radiolabeled with (64)Cu(II) rapidly under mild conditions and with higher specific activity than scFvanti-LIBS-DOTA.

Oral treatment with Cu(II)(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis.

Mutations in the metallo-protein Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans and an expression level-dependent phenotype in transgenic rodents. We show that oral treatment with the therapeutic agent diacetyl-bis(4-methylthiosemicarbazonato)copper(II) [Cu(II)(atsm)] increased the concentration of mutant SOD1 (SOD1G37R) in ALS model mice, but paradoxically improved locomotor function and survival of the mice. To determine why the mice with increased levels of mutant SOD1 had an improved phenotype, we analyzed tissues by mass spectrometry.

Enzyme-mediated site-specific bioconjugation of metal complexes to proteins: sortase-mediated coupling of copper-64 to a single-chain antibody.

The enzyme-mediated site-specific bioconjugation of a radioactive metal complex to a single-chain antibody using the transpeptidase sortase A is reported. Cage amine sarcophagine ligands that were designed to function as substrates for the sortase A mediated bioconjugation to antibodies were synthesized and enzymatically conjugated to a single-chain variable fragment. The antibody fragment scFv(anti-LIBS) targets ligand-induced binding sites (LIBS) on the glycoprotein receptor GPIIb/IIIa, which is present on activated platelets.