Targeted Auger Therapy represents great potential for the therapy of diseases which require a high degree of selectivity on the cellular level (e.g. for therapy of metastatic cancers). Due to their ...high Linear Energy Transfer (LET), Auger emitters, combined with selective biological systems which enable delivery of radionuclides close to the DNA of the targeting cell, can be extremely selective and powerful treatment tools. There are two main aspects associated with the development of efficient radiopharmaceuticals based on Auger Emitters: a) the availability of suitable Auger-emitting radionuclides for therapy and b) the design of targeting vectors which can deliver Auger emitters into/close to the nucleus. In the present review, we address the first aspect by defining important parameters for the selection of radionuclides for application to Targeted Auger Therapy and form a categorized list of the most promising radionuclides, their possible production routes, and their use in the synthesis of radiopharmaceuticals.
The use of α-emitting radionuclides in targeted alpha therapy (TAT) holds great potential for treatment of human diseases, such as cancer, due to the short pathlength and high potency of the α ...particle, which can localize damage to targeted cells while minimizing effects to healthy surrounding tissues. In this review several potential α-emitting radionuclides having emission properties applicable to TAT are discussed from a radiochemical point of view. Overviews of production, radiochemical separation and chelation aspects relative to developing TAT radiopharmaceuticals are provided for the α-emitting radionuclides (and their generator systems)
At,
Ra/
Pb/
Bi,
Ac/
Bi,
Th/
Ra,
U/
Th,
Tb and
Fm.
The 18‐membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all ...225Ac (26 kBq) in 5 min at RT. 225Ac(macropa)+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa‐NCS, was conjugated to trastuzumab as well as to the prostate‐specific membrane antigen‐targeting compound RPS‐070. Both constructs rapidly radiolabeled 225Ac in just minutes at RT, and macropa‐Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac‐macropa‐RPS‐070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft‐tissue metastases.
Actinium in action! A macrocyclic ligand exhibits unprecedented radiolabeling efficiency for the large α‐emitting radionuclide 225Ac3+. This ligand is extremely promising for the implementation of 225Ac in targeted alpha therapy for cancer. RCY=radiochemical yield.
Nuclear medicine leverages different types of radiometals for disease diagnosis and treatment, but these applications usually require them to be stably chelated. Given the often-disparate chemical ...properties of these radionuclides, it is challenging to find a single chelator that binds all of them effectively. Toward addressing this problem, we recently reported a macrocyclic chelator macrodipa with an unprecedented “dual-size-selectivity” pattern for lanthanide (Ln3+) ions, characterized by its high affinity for both the large and the small Ln3+ ( J. Am. Chem. Soc, 2020, 142, 13500 ). Here, we describe a second-generation “macrodipa-type” ligand, py-macrodipa. Its coordination chemistry with Ln3+ was thoroughly investigated experimentally and computationally. These studies reveal that the Ln3+–py-macrodipa complexes exhibit enhanced thermodynamic and kinetic stabilities compared to Ln3+–macrodipa, while retaining the unusual dual-size selectivity. Nuclear medicine applications of py-macrodipa for chelating radiometals with disparate chemical properties were assessed using the therapeutic 135La3+ and diagnostic 44Sc3+ radiometals representing the two size extremes within the rare-earth series. Radiolabeling and stability studies demonstrate that the rapidly formed complexes of these radionuclides with py-macrodipa are highly stable in human serum. Thus, in contrast to gold standard chelators like DOTA and macropa, py-macrodipa can be harnessed for the simultaneous, efficient binding of radiometals with disparate ionic radii like La3+ and Sc3+, signifying a substantial achievement in nuclear medicine. This concept could enable the facile incorporation of a breadth of medicinally relevant radiometals into chemically identical radiopharmaceutical agents. The fundamental coordination chemistry learned from py-macrodipa provides valuable insight for future chelator development.
The radionuclide 213Bi 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 Bi3+ complexes by NMR spectroscopy, mass spectrometry, and elemental analysis. Solid-state structures of three complexes revealed distorted coordination geometries about the Bi3+ center arising from the stereochemically active 6s2 lone pair. The kinetic properties of the Bi3+ complexes were assessed by challenging them with a 1000-fold excess of the chelating agent diethylenetriaminepentaacetic acid (DTPA). The most kinetically inert complexes contained the most basic pendent donors. Density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations were employed to investigate this trend, suggesting that the kinetic inertness is not correlated with the extent of the 6s2 lone pair stereochemical activity, but with the extent of covalency between pendent donors. Lastly, radiolabeling studies of 213Bi (30–210 kBq) with three of the most promising ligands showed rapid formation of the radiolabeled complexes at room temperature within 8 min for ligand concentrations as low as 10–7 M, corresponding to radiochemical yields of >80%, thereby demonstrating the promise of this ligand class for use in 213Bi TAT.
44Sc is an attractive positron-emitting radionuclide for PET imaging; herein, a new complex of the Sc3+ ion with nonmacrocyclic chelator H4pypa was synthesized and characterized with high-resolution ...electrospray-ionization mass spectrometry (HR-ESI-MS), as well as different nuclear magnetic resonance (NMR) spectroscopic techniques (1H, 13C, 1H–13C HSQC, 1H–13C HMBC, COSY, and NOESY). In aqueous solution (pH = 7), Sc(pypa)− presented two isomeric forms, the structures of which were predicted using density functional theory (DFT) calculation with a small energy difference of 22.4 kJ/mol, explaining their coexistence. Sc(pypa)− was found to have superior thermodynamic stability (pM = 27.1) compared to Sc(AAZTA)− (24.7) and Sc(DOTA)− (23.9). In radiolabeling, 44ScSc(pypa)− formed efficiently at RT in 15 min over a range of pH (2–5.5), resulting in a complex that is highly stable (>99%) in mouse serum over at least six half-lives of scandium-44. Similar labeling efficiency was observed with the PSMA (prostate-specific membrane antigen)-targeting H4pypa-C7-PSMA617 at pH = 5.5 (RT, 15 min), confirming negligible disturbance from the bifunctionalization on scandium-44 scavenging. Moreover, the kinetic inertness of the radiocomplex was proved in vivo. Surprisingly, the molar activity was found to have profound influence on the pharmacokinetics of the radiotracers where lower molar activity drastically reduced the background accumulations, particularly, kidney, and thus, yielded a much higher tumor-to-background contrast.
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
TbTb
and
TbTb
, and to assess the imaging and pharmacokinetic properties of each radiotracer in tumour-bearing mice.
TbTb-crown-TATE and
TbTb-crown-TATE were prepared efficiently under mild conditions, and exhibited excellent stability in human serum (>99.5% RCP over 7 days). Longitudinal SPECT/CT images were acquired for
Tb- and
Tb- labelled crown-TATE in male NRG mice bearing AR42J tumours. The radiotracers,
TbTb-crown-TATE and
TbTb-crown-TATE, showed high tumour targeting (32.6 and 30.0 %ID/g, respectively) and minimal retention in non-target organs at 2.5 h post-administration. Biodistribution studies confirmed the SPECT/CT results, showing high tumour uptake (38.7 ± 8.0 %ID/g and 38.5 ± 3.5 %ID/g, respectively) and favourable tumour-to-background ratios. Blocking studies further confirmed SSTR2-specific tumour accumulation. Overall, these findings suggest that crown-TATE has great potential for element-matched molecular imaging and radionuclide therapy using
Tb and
Tb.
A new method has been developed for the isolation of
Ra, in high yield and purity, from a proton irradiated
Th matrix. Herein we report an all-aqueous process using multiple solid-supported ...adsorption steps including a citrate chelation method developed to remove >99.9% of the barium contaminants by activity from the final radium product. A procedure involving the use of three columns in succession was developed, and the separation of
Ra from the thorium matrix was obtained with an overall recovery yield of 91 ± 3%, average radiochemical purity of 99.9%, and production yields that correspond to physical yields based on previously measured excitation functions.
Actinium-225 is a potential Targeted Alpha Therapy (TAT) isotope. It can be generated with high energy (≥ 100MeV) proton irradiation of thorium targets. The main challenge in the chemical recovery of ...225Ac lies in the separation from thorium and many fission by-products most importantly radiolanthanides. We recently developed a separation strategy based on a combination of cation exchange and extraction chromatography to isolate and purify 225Ac. In this study, actinium and lanthanide equilibrium distribution coefficients and column elution behavior for both TODGA (N,N,N′,N′-tetra-n-octyldiglycolamide) and TEHDGA (N,N,N′,N′-tetrakis-2-ethylhexyldiglycolamide) were determined. Density functional theory (DFT) calculations were performed and were in agreement with experimental observations providing the foundation for understanding of the selectivity for Ac and lanthanides on different DGA (diglycolamide) based resins. The results of Gibbs energy (ΔGaq) calculations confirm significantly higher selectivity of DGA based resins for LnIII over AcIII in the presence of nitrate. DFT calculations and experimental results reveal that Ac chemistry cannot be predicted from lanthanide behavior under comparable circumstances.
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•Measurement of Ac3+, Eu3+ and Lu3+ distribution coefficients for resins TODGA/TEHDGA in HCl/HNO3.•DFT modeling for Ac, Eu, Lu was carried out assuming a model ligand tetramethyl-diglycolamide.•Gibbs energy calculations confirm higher DGA selectivity for LnIII over AcIII in nitrate media.•Dynamic column methods were designed for the separation of 225Ac from Th, Ra and Ln.•Analytical and preparative procedures for the separation of 225Ac from Th, Ra and Ln were developed.
Targeted Radionuclide Therapies (TRTs) based on Auger emitting radionuclides have the potential to deliver extremely selective therapeutic payloads on the cellular level. However, to fully exploit ...this potential, suitable radionuclides need to be applied in combination with appropriate delivery systems. In this review, we summarize the state-of-the-art production, purification, chelation and applications of two promising candidates for Targeted Auger Therapy, namely antimony- 119 (
Sb) and mercury-197 (
Hg). Both radionuclides have great potential to become efficient tools for TRT. We also highlight our current progress on the production of both radionuclides at TRIUMF and the University of Wisconsin.
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