Radioisotopes of fluorine (F), scandium (Sc, Sc), lutetium (Lu), and yttrium (Y, Y) have decay properties ideally suited for targeted nuclear imaging and therapy with small biologics, such as peptides and antibody fragments. However, a single-molecule strategy to introduce these radionuclides into radiopharmaceuticals under mild conditions to afford inert in vivo complexes is critically lacking. Here, we introduce HL2 and HL3, two small-cavity macrocyclic chelator structural isomers bearing a single phosphonate functional group.
View Article and Find Full Text PDFWe present a detailed investigation of the coordination chemistry toward [Cu/Cu]copper of a series of HDEDPA derivatives (HDEDPA = 6,6'-((ethane-1,2-diylbis(azanediyl))bis(methylene))dipicolinic acid) containing cyclohexyl (HCHXDEDPA), cyclopentyl (HCpDEDPA) or cyclobutyl (HCBuDEDPA) spacers. Furthermore, we also developed a strategy that allowed the synthesis of a HCBuDEDPA analogue containing an additional NHBoc group at the cyclobutyl ring, which can be used for conjugation to targeting units. The X-ray structures of the Cu(II) complexes evidence distorted octahedral coordination around the metal ion in all cases.
View Article and Find Full Text PDFThe widely established PET isotope F does not have a therapeutic partner. We have recently established that the Sc-F bond can be formed under aqueous, high yielding conditions, paving the way to providing F as diagnostic partners to Sc and Lu radiotherapeutics. Here, we synthesized a library of tacn-based chelators comprised of 10 structurally unique permutations incorporating acetate, methyl-benzylamide and picolinate donor arms.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
December 2024
The elementally matched Co (t=17.53 h, I=77 %)/Co (t=9.10 h, internal conversion=100 %) radioisotope pair is of interest for development of paired diagnostic/therapeutic radiopharmaceuticals.
View Article and Find Full Text PDFNuclear medicine harnesses radioisotopes for the diagnosis and treatment of disease. While the isotopes Tc and In have enabled the clinical diagnosis of millions of patients over the past 3 decades, more recent clinical translation of numerous Ga/Lu-based radiopharmaceuticals for diagnostic imaging and therapy underscores the clinical utility of metal-based radiopharmaceuticals in mainstream cancer treatment. In addition to such established radionuclides, advancements in radioisotope production have enabled the production of radionuclides with a broad range of half-lives and emission properties of interest for nuclear medicine.
View Article and Find Full Text PDFTo harness radiometals in clinical settings, a chelator forming a stable complex with the metal of interest and targets the desired pathological site is needed. Toward this goal, we previously reported a unique set of chelators that can stably bind to both large and small metal ions, via a conformational switch. Within this chelator class, py-macrodipa is particularly promising based on its ability to stably bind several medicinally valuable radiometals including large La, Bi, and small Sc.
View Article and Find Full Text PDFThe development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide Ti for radiopharmaceutical applications. Herein, we evaluate the Ti-coordination chemistry of four catechol-based, hexacoordinate chelators using synthetic, structural, computational, and radiochemical approaches. The siderophore enterobactin (Ent) and its synthetic mimic TREN-CAM readily form mononuclear Ti species in aqueous solution at neutral pH.
View Article and Find Full Text PDFRecent Food and Drug Administration (FDA) approval of diagnostic and therapeutic radiopharmaceuticals and concurrent miniaturization of particle accelerators leading to improved access has fueled interest in the development of chemical transformations suitable for short-lived radioactive isotopes on the tracer scale. This recent renaissance of radiochemistry is paired with new opportunities to study fundamental chemical behavior and reactivity of elements to improve their production, separation, and incorporation into bioactive molecules to generate new radiopharmaceuticals. This outlook outlines pertinent challenges in the field of radiochemistry and indicates areas of opportunity for chemical discovery and development, including those of clinically established (C-11, F-18) and experimental radionuclides in preclinical development across the periodic table.
View Article and Find Full Text PDFDiscrete luminescent lanthanide complexes represent a potential alternative to organic chromophores due to their tunability of optical properties, insensitivity to photobleaching, and large pseudo-Stokes shifts. Previously, we demonstrated that the lack of depth penetration of UV excitation required to sensitize discrete terbium and europium complexes can be overcome using Cherenkov radiation emitted by clinically employed radioisotopes in situ. Here, we show that the second-generation europium complexes [Eu(pcta-PEPA)] and [Eu(tacn-pic-PEPA)] (Φ = 57% and 76%, respectively) lower the limit of detection (LoD) to 1 nmol in the presence of 10 μCi of Cherenkov emitting isotopes, F and Ga.
View Article and Find Full Text PDFWe synthesized, thanks to the regiospecific -functionalization using an orthoamide intermediate, two 1,4,7-triazacyclononane derivatives containing an acetate arm and either a methylpyridine or a picolinic acid group, respectively, H and H, as new Ga chelators for potential use in nuclear medicine. The corresponding Ga complexes were synthesized and structurally characterized in solution by H and C NMR. The [Ga()] complex appears to exist in solution as two diasteroisomeric pairs of enantiomers, as confirmed by density functional theory (DFT) calculations, while for [Ga()], a single species is present in solution.
View Article and Find Full Text PDFThe solution chemistry of the hydrolytic, early-transition-metal ions Ti and Sc represents a coordination chemistry challenge with important real-world implications, specifically in the context of Ti/Sc and Ti/Sc radiochemical separations. Unclear speciation of the solid and solution phases and tertiary mixtures of mineral acid, organic chelators, and solid supports are common confounds, necessitating tedious screening of multiple variables. Herein we describe how thermodynamic speciation data in solution informs the design of new solid-phase chelation approaches enabling separations of Ti and Sc.
View Article and Find Full Text PDFActivation of metalloprodrugs or prodrug activation using transition metal catalysts represents emerging strategies for drug development; however, they are frequently hampered by poor spatiotemporal control and limited catalytic turnover. Here, we demonstrate that metal complex-mediated, autolytic release of active metallodrugs can be successfully employed to prepare clinical grade (radio-)pharmaceuticals. Optimization of the Lewis-acidic metal ion, chelate, amino acid linker, and biological targeting vector provides means to release peptide-based (radio-)metallopharmaceuticals in solution and from the solid phase using metal-mediated, autolytic amide bond cleavage (MMAAC).
View Article and Find Full Text PDFChlorotoxin (CTX), a scorpion venom-derived 36-residue miniprotein, binds to and is taken up selectively by glioblastoma cells. Previous studies provided controversial results concerning target protein(s) of CTX. These included CLC3 chloride channel, matrix metalloproteinase 2 (MMP-2), regulators of MMP-2, annexin A2, and neuropilin 1 (NRP1).
View Article and Find Full Text PDFShort-lived, radioactive lanthanides comprise an emerging class of radioisotopes attractive for biomedical imaging and therapy applications. To deliver such isotopes to target tissues, they must be appended to entities that target antigens overexpressed on the target cell's surface. However, the thermally sensitive nature of biomolecule-derived targeting vectors requires the incorporation of these isotopes without the use of denaturing temperatures or extreme pH conditions; chelating systems that can capture large radioisotopes under mild conditions are therefore highly desirable.
View Article and Find Full Text PDFThe efficient, large-scale synthesis of radiometallated radiopharmaceuticals represents an emerging clinical need which, to date, is inherently limited by time consuming, sequential procedures to conduct isotope separation, radiochemical labeling and purification prior to formulation for injection into the patient. In this work, we demonstrate that a solid-phase based, concerted separation and radiosynthesis strategy followed by photochemical release of radiotracer in biocompatible solvents can be employed to prepare ready-to-inject, clinical grade radiopharmaceuticals. Optimization of resin base, resin loading, and radiochemical labeling capacity are demonstrated with Ga and Cu radioisotopes using a short model peptide sequence and further validated using two peptide-based radiopharmaceuticals with clinical relevance, targeting the gastrin-releasing peptide and the prostate specific membrane antigen.
View Article and Find Full Text PDFIntroduction: Acute gastrointestinal bleeding (GIB) is a life-threatening emergency with a critical economic burden. As a result of bleeding, anaemia often requires intravenous or oral iron supplementation. Elderly patients are even more prone to untoward outcomes after hospital discharge if iron supplementation is inefficient.
View Article and Find Full Text PDFRadioisotopes of Cu, such as Cu and Cu, are alluring targets for imaging (e.g., positron emission tomography, PET) and radiotherapeutic applications.
View Article and Find Full Text PDFThe nine-coordinate aza-macrocycle DO3Apic-NO2 and its kinetically inert rare earth complexes [M(DO3A-pic-NO2)]- (M = La, Tb, Eu, Lu, Y) can be readily bioconjugated to surface accessible thioles on peptides and proteins with a minimal structural footprint. All complexes express thioconjugation rate constants in the same order of magnitude ( = 0.3 h) with the exception of Sc ( = 0.
View Article and Find Full Text PDFMedicinal inorganic chemistry is a burgeoning subfield of medicinal chemistry that focuses on the development of metal-based diagnostic and therapeutic agents. This tutorial review aims to provide an introductory primer, present a timely overview of recent discoveries and identify current challenges and opportunities of the field. Three specific areas of discovery are highlighted herein.
View Article and Find Full Text PDFAn immunosuppressive tumor microenvironment and tumor heterogeneity have led to the resilience of metastatic castrate resistant prostate cancer (mCRPC) to current treatments. To address these challenges, we developed and evaluated a new drug paradigm, Radio-IMmunostimulant (RIMS), in a syngeneic model of murine prostate cancer. RIMS-1 was generated using a convergent synthesis employing solid phase peptide and solution chemistries.
View Article and Find Full Text PDFPancreatic necrosis is a consistent prognostic factor in acute pancreatitis (AP). However, the clinical scores currently in use are either too complicated or require data that are unavailable on admission or lack sufficient predictive value. We therefore aimed to develop a tool to aid in necrosis prediction.
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