The HSmacropa Series: Increasing the Chemical Softness of Hmacropa with Sulfur Atoms to Chelate Radiometals [Bi]Bi and [Pb]Pb for Radiopharmaceutical Applications.

The effects of replacing nitrogen with sulfur atoms in the 18-membered macrocycle of the Hmacropa chelator on the binding affinity and stability of "intermediate" (radio)metal [Pb]Pb and [Bi]Bi complexes are investigated. The 1,4,10,13-tetraoxo-7,16-diazacyclooctadecane backbone was replaced with derivatives containing sulfur in the 1,4- or the 1,4,10,13-positions to yield the novel chelators HSmacropa (NOS) and HSmacropa (NOS), respectively. Trends on the Pb- and Bi-complex stability constants, coordination chemistry, radiolabeling, and kinetic inertness were assessed via potentiometric titrations, UV-vis spectroscopy, NMR spectroscopy, X-ray crystallography and density functional theory (DFT) calculations.

Preclinical Evaluation of Ac as a Theranostic Agent: Imaging, Dosimetry, and Therapy.

Ac (t = 29.37 h) has been proposed as a theranostic radioisotope leveraging both its diagnostic γ-emissions and therapeutic α-emissions. Ac emits 158 and 230 keV γ-photons ideal for quantitative SPECT imaging and acts as an in vivo generator of 4 high-energy α-particles.

Quantitative SPECT imaging of Tb and Tb for preclinical theranostic radiopharmaceutical development.

Background: Element-equivalent matched theranostic pairs facilitate quantitative in vivo imaging to establish pharmacokinetics and dosimetry estimates in the development of preclinical radiopharmaceuticals. Terbium radionuclides have significant potential as matched theranostic pairs for multipurpose applications in nuclear medicine. In particular, Tb (t = 5.

Preclinical evaluation of [Ac]Ac-crown-TATE - An alpha-emitting radiopharmaceutical for neuroendocrine tumors.

Background: Targeted alpha therapy (TAT) of somatostatin receptor-2 (SSTR2) positive neuroendocrine tumors (NETs) involving Ac-225 ([Ac]Ac-DOTA-TATE) has previously demonstrated improved therapeutic efficacy over conventional beta particle-emitting peptide receptor radionuclide therapy agents. DOTA-TATE requires harsh radiolabeling conditions for chelation of [Ac]Ac, which can limit the achievable molar activities and thus therapeutic efficacy of such TAT treatments. Macropa-TATE was recently highlighted as a potential alternative to DOTA-TATE, owing to the mild radiolabeling conditions and high affinity toward [Ac]Ac; however, elevated liver and kidney uptake were noted as a major limitation and a suitable imaging radionuclide is yet to be reported, which will be required for patient dosimetry studies and assessment of therapeutic benefit.

quantitative SPECT imaging of actinium-226: feasibility and proof-of-concept.

.Ac radiopharmaceuticals have tremendous potential for targeted alpha therapy, however,Ac (= 9.9 d) lacks direct gamma emissions forimaging.

Preclinical evaluation of MC1R targeting theranostic pair [Tb]Tb-crown-αMSH and [Tb]Tb-crown-αMSH.

Background: Targeted radionuclide therapy is established as a highly effective strategy for the treatment of metastatic tumors; however, the co-development of suitable imaging companions to therapy remains significant challenge. Theranostic isotopes of terbium (Tb, Tb, Tb, Tb) have the potential to provide chemically identical radionuclidic pairs, which collectively encompass all modes of nuclear decay relevant to nuclear medicine. Herein, we report the first radiochemistry and preclinical studies involving Tb- and Tb-labeled crown-αMSH, a small peptide-based bioconjugate suitable for targeting melanoma.

Rearmed Bifunctional Chelating Ligand for Ac/Tb Precision-Guided Theranostic Radiopharmaceuticals─HnoneunpaX.

Superior bifunctional chelating ligands, which can sequester both α-emitting radionuclides (Ac, Bi) and their diagnostic companions (Tb, In), remain a formidable challenge to translating targeted alpha therapy, with complementary diagnostic imaging, to the clinic. HnoneupaX, a chelating ligand with an unusual diametrically opposed arrangement of pendant donor groups, has been developed to this end. HnoneunpaX preferentially complexes Ln and An ions, forming thermodynamically stable (pLa = 17.

Separation of Sc/Sc Nuclear Isomers Based on After-Effects.

Sc presents a particular interest for application in nuclear medicine for positron emission tomography (PET) due to its favorable nuclear decay properties ( = 3.97 h, = 1.47 MeV, branching ratio 94.

Preclinical Evaluation of [Tb]Tb-Crown-TATE-A Novel SPECT Imaging Theranostic Agent Targeting Neuroendocrine Tumours.

Terbium radioisotopes (Tb, Tb, Tb, Tb) offer a unique class of radionuclides which encompass all four medicinally relevant nuclear decay modalities (α, , γ, /e), and show high potential for the development of element-matched theranostic radiopharmaceuticals. The goal of this study was to design, synthesise, and evaluate the suitability of crown-TATE as a new peptide-conjugate for radiolabelling of [Tb]Tb and [Tb]Tb, and to assess the imaging and pharmacokinetic properties of each radiotracer in tumour-bearing mice. [Tb]Tb-crown-TATE and [Tb]Tb-crown-TATE were prepared efficiently under mild conditions, and exhibited excellent stability in human serum (>99.

HTPAN-Triazole-Bn-NH: Tripicolinate Clicked-Bifunctional Chelate for [Ac]/[In] Theranostics.

A new, high-denticity, bifunctional ligand─HTPAN-triazole-Bn-NH─has been synthesized and studied in complexation with [Ac]Ac and [In]In for radiopharmaceutical applications. The bifunctional chelator is readily synthesized, using a high-yielding four-step prep, which is highly adaptable and allows for straightforward incorporation of different covalent linkers using Cu-catalyzed alkyne-azide cycloaddition (click) chemistry. Nuclear magnetic resonance (NMR) studies of HTPAN-triazole-Bn-NH with La and In metal ions show the formation of a single, asymmetric complex with each ion in solution, corroborated by density functional theory (DFT) calculations.

Hpicoopa─Robust Chelate for Ac/In Theranostics.

The nuclear decay characteristics of Ac ( = 5-8 MeV, linear energy transfer (LET) = ∼100 keV/μm, = 9.92 days) are well recognized as advantageous for the treatment of primary and metastatic tumors; however, suitable chelation systems are required, which can accommodate this radiometal. Since Ac does not possess any suitable low-energy, high abundance γ-ray emissions for nuclear imaging, there is a clear need for the development of other companion radionuclides with similar coordination characteristics and comparable half-lives, which can be applied in diagnostics.

Trastuzumab-conjugated oxine-based ligand for [Zr]Zr immunoPET.

A new, bifunctional chelating ligand for immuno-Positron Emission Tomography (PET) was designed, synthesized, and conjugated to Trastuzumab for a proof-of-concept study with Zr. Hneunox was synthesized from the tris(2-aminoethyl)amine backbone, decorated with 8-hydroxyquinoline moieties, and utilizes a primary amine for functionalization. A maleimide moiety extends the chelator to create Hneunox-mal for antibody conjugation via maleimide-thiol click chemistry.

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.

Hampa─Versatile Chelator for [Pb]Pb, [Bi]Bi, and [Ac]Ac.

A new decadentate chelator, Hampa, was designed to be a potential radiopharmaceutical chelator component. The chelator involves both amide and picolinate functional groups on a large non-macrocyclic, ether-bridged backbone. With its large scaffold, Hampa was paired with [Pb]Pb, [Bi]Bi, and La/[Ac]Ac ions.

Bis(amido)bis(oxinate)diamine Ligands for theranostic radiometals.

With the interest in radiometal-containing diagnostic and therapeutic pharmaceuticals increasing rapidly, appropriate ligands to coordinate completely and stably said radiometals is essential. Reported here are two novel, bis(amido)bis(oxinate)diamine ligands, Hamidohox (2,2'-(ethane-1,2-diylbis(((8-hydroxyquinolin-2-yl)methyl)azanediyl))diacetamide) and HamidoC3hox (2,2'-(propane-1,3-diylbis(((8-hydroxyquinolin-2-yl)methyl)azanediyl))diacetamide), that combine two 8-hydroxyquinoline and amide donor groups and differ by one carbon in their 1,2-ethylenediamine vs. 1,3-diaminopropane backbones, respectively.

[Bi]Bi/[In]In-neunpa-cycMSH: Theranostic Radiopharmaceutical Targeting Melanoma─Structural, Radiochemical, and Biological Evaluation.

With the emergence of [Ac]Ac as a therapeutic radionuclide for targeted α therapy (TAT), access to clinical quantities of the potent, short-lived α-emitter [Bi]Bi ( = 45.6 min) will increase over the next decade. With this in mind, the nonadentate chelator, Hneunpa-NH, has been investigated as a ligand for chelation of [Bi]Bi in combination with [In]In as a suitable radionuclidic pair for TAT and single photon emission computed tomography (SPECT) diagnostics.

Chelating the Alpha Therapy Radionuclides Ac and Bi with 18-Membered Macrocyclic Ligands Macrodipa and Py-Macrodipa.

The radionuclides Ac and Bi possess favorable physical properties for targeted alpha therapy (TAT), a therapeutic approach that leverages α radiation to treat cancers. A chelator that effectively binds and retains these radionuclides is required for this application. The development of ligands for this purpose, however, is challenging because the large ionic radii and charge-diffuse nature of these metal ions give rise to weaker metal-ligand interactions.

Radiolabeling of a polypeptide polymer for intratumoral delivery of alpha-particle emitter, Ac, and beta-particle emitter, Lu.

Introduction: Radiotherapy of cancer requires both alpha- and beta-particle emitting radionuclides, as these radionuclide types are efficient at destroying different types of tumors. Both classes of radionuclides require a vehicle, such as an antibody or a polymer, to be delivered and retained within the tumor. Polyglutamic acid (pGlu) is a polymer that has proven itself effective as a basis of drug-polymer conjugates in the clinic, while its derivatives have been used for pretargeted tumor imaging in a research setup.

Hpyhox - Octadentate Bis(pyridyloxine).

A new versatile chelating ligand for intermediate size and softness radiometals [Cu]Cu and [In]In, Hpyhox, was synthesized by introducing pyridine as a new donor moiety to complement 8-hydroxyquinoline on an ethylenediamine backbone. The combination of pyridine and oxine as donor sets was explored through structural analysis, and crystals of the three metal complexes with Cu, La, and In demonstrate how the ligand adapts to accommodate metal ions of different sizes and charge. Exhaustive in-batch UV solution studies characterized the protonation constants of the free ligand as well as the formation constants of the metal complexes with Cu, In, and La.

Tuning the Kinetic Inertness of Bi Complexes: The Impact of Donor Atoms on Diaza-18-Crown-6 Ligands as Chelators for Bi Targeted Alpha Therapy.

The radionuclide Bi can be applied for targeted α therapy (TAT): a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To use this radionuclide for this application, a bifunctional chelator (BFC) is needed to attach it to a biological targeting vector that can deliver it selectively to cancer cells. Here, we investigated six macrocyclic ligands as potential BFCs, fully characterizing the Bi complexes by NMR spectroscopy, mass spectrometry, and elemental analysis.

Chemical Promiscuity of Non-Macrocyclic Multidentate Chelating Ligands for Radiometal Ions: Hneunpa-NH Hnoneunpa.

A comparative investigation of two structurally related potentially nonadentate chelating ligands, Hneunpa-NH and Hnoneunpa, has been undertaken to examine the influence of bifunctionalization on their coordination chemistry and metal ion selectivity. Significantly improved synthetic routes for each compound have been developed, employing straightforward high-yielding strategies. Radiolabeling studies with [Sc]Sc, [In]In, [Lu]Lu, and [Ac]Ac revealed a sharp contrast between the affinity of each chelator for large radiometal ions.

High denticity oxinate-linear-backbone chelating ligand for diagnostic radiometal ions [In]In and [Zr]Zr.

Advances in nuclear medicine depend on chelating ligands that form highly stable and kinetically inert complexes with relevant radiometal ions for use in diagnosis or therapy. A new potentially decadentate ligand, Hdecaox, was synthesised to incorporate two 8-hydroxyquinoline moieties on either end of a diethylenetriamine backbone decorated with three carboxylic acids, one at each N atom of the backbone. Metal complexation was assessed using nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HR-MS) with In, Zr and La.

Magnetic high throughput screening system for the development of nano-sized molecularly imprinted polymers for controlled delivery of curcumin.

Curcumin is a versatile anti-inflammatory and anti-cancer agent known for its low bioavailability, which could be improved by developing materials capable of binding and releasing drug in a controlled fashion. The present study describes the preparation of magnetic nano-sized Molecularly Imprinted Polymers (nanoMIPs) for the controlled delivery of curcumin and their high throughput characterisation using microtitre plates modified with magnetic inserts. NanoMIPs were synthesised using functional monomers chosen with the aid of molecular modelling.