Nuclear medicine is a rapidly evolving multidisciplinary research field that has been intensively investigated in the past decades. The successful clinical application of various metal‐based radiopharmaceuticals for cancer imaging and therapy is based on the modular assembly of the drug complex through the popular bifunctional chelate (BFC) strategy. In targeted radionuclide therapy (TRT), potent radiation is selectively delivered to the cancer cells using radiopharmaceuticals that incorporate therapeutic radiometals which emit α ‐particles, β − ‐particles, or Meitner–Auger electrons (MAEs). Radiotheranostics is an emerging concept that connects nuclear imaging (via positron emission tomography (PET) or single‐photon emission computed tomography (SPECT)) and therapy for personalized cancer diagnosis and treatment. This article outlines the fundamentals of radiopharmaceutical design and radiotheranostics and presents a general description of the therapeutic emissions accompanied by literature examples of the most promising radionuclides; 212 Pb, 213 Bi, 225 Ac, 227 Th, and 149 Tb for α therapy; 47 Sc, 67 Cu, 77 As, and 161 Tb for β − therapy; and 119 Sb, 135 La, and 197m/g Hg for MAE therapy. A comparison of the currently used or proposed theranostic pairs of each radiometal is presented.
In this work, a pair of gold(III) complexes derived from the analogous tetrapyridyl ligands H 2 biqbpy1 and H 2 biqbpy2 was prepared: the rollover, bis-cyclometalated [Au(biqbpy1)Cl ([1]Cl) and its isomer [Au(biqbpy2)Cl ([2]Cl). In [1] + , two pyridyl rings coordinate to the metal via a Au–C bond (C ∧ N ∧ N ∧ C coordination) and the two noncoordinated amine bridges of the ligand remain protonated, while in [2] + all four pyridyl rings of the ligand coordinate to the metal via a Au–N bond (N ∧ N ∧ N ∧ N coordination), but both amine bridges are deprotonated. As a result, both complexes are monocationic, which allowed comparison of the sole effect of cyclometalation on the chemistry, protein interaction, and anticancer properties of the gold(III) compounds. Due to their identical monocationic charge and similar molecular shape, both complexes [1]Cl and [2]Cl displaced reference radioligand [ 3 H]dofetilide equally well from cell membranes expressing the K v 11.1 (hERG) potassium channel, and more so than the tetrapyridyl ligands H 2 biqbpy1 and H 2 biqbpy2. By contrast, cyclometalation rendered [1]Cl coordinatively stable in the presence of biological thiols, while [2]Cl was reduced by a millimolar concentration of glutathione into metastable Au(I) species releasing the free ligand H 2 biqbpy2 and TrxR-inhibiting Au + ions. The redox stability of [1]Cl dramatically decreased its thioredoxin reductase (TrxR) inhibition properties, compared to [2]Cl. On the other hand, unlike [2]Cl, [1]Cl aggregated into nanoparticles in FCS-containing medium, which resulted in much more efficient gold cellular uptake. [1]Cl had much more selective anticancer properties than [2]Cl and cisplatin, as it was almost 10 times more cytotoxic to human cancer cells (A549, A431, A375, and MCF7) than to noncancerous cells (MRC5). Mechanistic studies highlight the strikingly different mode of action of the two compounds: while for [1]Cl high gold cellular uptake, nuclear DNA damage, and interaction with hERG may contribute to cell killing, for [2]Cl extracellular reduction released TrxR-inhibiting Au + ions that were taken up in minute amounts in the cytosol, and a toxic tetrapyridyl ligand also capable of binding to hERG. These results demonstrate that bis-cyclometalation is an appealing method to improve the redox stability of Au(III) compounds and to develop gold-based cytotoxic compounds that do not rely on TrxR inhibition to kill cancer cells.
Radiolanthanides and actinides are aptly suited for the diagnosis and treatment of cancer via nuclear medicine because they possess unique chemical and physical properties (e.g., radioactive decay emissions). These rare radiometals have recently shown the potential to selectively deliver a radiation payload to cancer cells. However, their clinical success is highly dependent on finding a suitable ligand for stable chelation and conjugation to a diseasetargeting vector. Currently, the commercially available chelates exploited in the radiopharmaceutical design do not fulfill all of the requirements for nuclear medicine applications, and there is a need to further explore their chemistry to rationally design highly specific chelates. Herein, we describe the rational design and chemical development of a novel decadentate acyclic chelate containing five 1,2hydroxypyridinones, 3,4,3,3-(LI-1,2-HOPO), referred to herein as HOPO-O 10 , based on the well-known octadentate ligand 3,4,3-(LI-1,2-HOPO), referred to herein as HOPO-O 8 , a highly efficient chelator for 89 Zr[Zr 4+ ]. Analysis by 1 H NMR spectroscopy and mass spectrometry of the La 3+ and Tb 3+ complexes revealed that HOPO-O 10 forms bimetallic complexes compared to HOPO-O 8 , which only forms monometallic species. The radiolabeling properties of both chelates were screened with [ 135 La]La 3+ , [ 155/161 Tb]Tb 3+ , [ 225 Ac]Ac 3+ and, [ 227 Th]Th 4+ . Comparable high specific activity was observed for the [ 155/161 Tb]Tb 3+ complexes, outperforming the gold-standard 1,4,7,10-tetraazacyclododecane-1,4,7,10tetraacetic acid, yet HOPO-O 10 surpassed HOPO-O 8 with higher [ 227 Th]Th 4+ affinity and improved complex stability in a human serum challenge assay. A comprehensive analysis of the decadentate and octadentate chelates was performed with density functional theory for the La 3+ , Ac 3+ , Eu 3+ , Tb 3+ , Lu 3+ , and Th 4+ complexes. The computational simulations demonstrated the enhanced stability of Th 4+ -HOPO-O 10 over Th 4+ -HOPO-O 8 . This investigation reveals the potential of HOPO-O 10 for the stable chelation of large tetravalent radioactinides for nuclear medicine applications and provides insight for further chelate development.
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