Exploring the Potential of High-Molar-Activity Samarium-153 for Targeted Radionuclide Therapy with [153Sm]Sm-DOTA-TATE.

Samarium-153 is a promising theranostic radionuclide, but low molar activities (Am) resulting from its current production route render it unsuitable for targeted radionuclide therapy (TRNT). Recent efforts combining neutron activation of 152Sm in the SCK CEN BR2 reactor with mass separation at CERN/MEDICIS yielded high-Am 153Sm. In this proof-of-concept study, we further evaluated the potential of high-Am 153Sm for TRNT by radiolabeling to DOTA-TATE, a well-established carrier molecule binding the somatostatin receptor 2 (SSTR2) that is highly expressed in gastroenteropancreatic neuroendocrine tumors. DOTA-TATE was labeled with 153Sm and remained stable up to 7 days in relevant media. The binding specificity and high internalization rate were validated on SSTR2-expressing CA20948 cells. In vitro biological evaluation showed that [153Sm]Sm-DOTA-TATE was able to reduce CA20948 cell viability and clonogenic potential in an activity-dependent manner. Biodistribution studies in healthy and CA20948 xenografted mice revealed that [153Sm]Sm-DOTA-TATE was rapidly cleared and profound tumor uptake and retention was observed whilst these were limited in normal tissues. This proof-of-concept study showed the potential of mass-separated 153Sm for TRNT and could open doors towards wider applications of mass separation in medical isotope production.

Bifunctional chelators for radiorhenium: past, present and future outlook.

Targeted radionuclide therapy (TRNT) is an ever-expanding field of nuclear medicine that provides a personalised approach to cancer treatment while limiting toxicity to normal tissues. It involves the radiolabelling of a biological targeting vector with an appropriate therapeutic radionuclide, often facilitated by the use of a bifunctional chelator (BFC) to stably link the two entities. The radioisotopes of rhenium, 186Re (t 1/2 = 90 h, 1.07 MeV ß-, 137 keV γ (9%)) and 188Re (t 1/2 = 16.9 h, 2.12 MeV ß-, 155 keV γ (15%)), are particularly attractive for radiotherapy because of their convenient and high-abundance ß--particle emissions as well as their imageable γ-emissions and chemical similarity to technetium. As a transition metal element with multiple oxidation states and coordination numbers accessible for complexation, there is great opportunity available when it comes to developing novel BFCs for rhenium. The purpose of this review is to provide a recap on some of the past successes and failings, as well as show some more current efforts in the design of BFCs for 186/188Re. Future use of these radionuclides for radiotherapy depends on their cost-effective availability and this will also be discussed. Finally, bioconjugation strategies for radiolabelling biomolecules with 186/188Re will be touched upon.

Radiolabeling of Human Serum Albumin With Terbium-161 Using Mild Conditions and Evaluation of in vivo Stability.

Targeted radionuclide therapy (TRNT) is a promising approach for cancer therapy. Terbium has four medically interesting isotopes (149Tb, 152Tb, 155Tb and 161Tb) which span the entire radiopharmaceutical space (TRNT, PET and SPECT imaging). Since the same element is used, accessing the various diagnostic or therapeutic properties without changing radiochemical procedures and pharmacokinetic properties is advantageous. The use of (heat-sensitive) biomolecules as vector molecule with high affinity and selectivity for a certain molecular target is promising. However, mild radiolabeling conditions are required to prevent thermal degradation of the biomolecule. Herein, we report the evaluation of potential bifunctional chelators for Tb-labeling of heat-sensitive biomolecules using human serum albumin (HSA) to assess the in vivo stability of the constructs. p-SCN-Bn-CHX-A"-DTPA, p-SCN-Bn-DOTA, p-NCS-Bz-DOTA-GA and p-SCN-3p-C-NETA were conjugated to HSA via a lysine coupling method. All HSA-constructs were labeled with [161Tb]TbCl3 at 40°C with radiochemical yields higher than 98%. The radiolabeled constructs were stable in human serum up to 24 h at 37°C. 161Tb-HSA-constructs were injected in mice to evaluate their in vivo stability. Increasing bone accumulation as a function of time was observed for [161Tb]TbCl3 and [161Tb]Tb-DTPA-CHX-A"-Bn-HSA, while negligible bone uptake was observed with the DOTA, DOTA-GA and NETA variants over a 7-day period. The results indicate that the p-SCN-Bn-DOTA, p-NCS-Bz-DOTA-GA and p-SCN-3p-C-NETA are suitable bifunctional ligands for Tb-based radiopharmaceuticals, allowing for high yield radiolabeling in mild conditions.

Production of Sm-153 With Very High Specific Activity for Targeted Radionuclide Therapy.

Samarium-153 (153Sm) is a highly interesting radionuclide within the field of targeted radionuclide therapy because of its favorable decay characteristics. 153Sm has a half-life of 1.93 d and decays into a stable daughter nuclide (153Eu) whereupon ß- particles [E = 705 keV (30%), 635 keV (50%)] are emitted which are suitable for therapy. 153Sm also emits γ photons [103 keV (28%)] allowing for SPECT imaging, which is of value in theranostics. However, the full potential of 153Sm in nuclear medicine is currently not being exploited because of the radionuclide's limited specific activity due to its carrier added production route. In this work a new production method was developed to produce 153Sm with higher specific activity, allowing for its potential use in targeted radionuclide therapy. 153Sm was efficiently produced via neutron irradiation of a highly enriched 152Sm target (98.7% enriched, σth = 206 b) in the BR2 reactor at SCK CEN. Irradiated target materials were shipped to CERN-MEDICIS, where 153Sm was isolated from the 152Sm target via mass separation (MS) in combination with laser resonance enhanced ionization to drastically increase the specific activity. The specific activity obtained was 1.87 TBq/mg (≈ 265 times higher after the end of irradiation in BR2 + cooling). An overall mass separation efficiency of 4.5% was reached on average for all mass separations. Further radiochemical purification steps were developed at SCK CEN to recover the 153Sm from the MS target to yield a solution ready for radiolabeling. Each step of the radiochemical process was fully analyzed and characterized for further optimization resulting in a high efficiency (overall recovery: 84%). The obtained high specific activity (HSA) 153Sm was then used in radiolabeling experiments with different concentrations of 4-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA). Even at low concentrations of p-SCN-Bn-DOTA, radiolabeling of 0.5 MBq of HSA 153Sm was found to be efficient. In this proof-of-concept study, we demonstrated the potential to combine neutron irradiation with mass separation to supply high specific activity 153Sm. Using this process, 153SmCl3 suitable for radiolabeling, was produced with a very high specific activity allowing application of 153Sm in targeted radionuclide therapy. Further studies to incorporate 153Sm in radiopharmaceuticals for targeted radionuclide therapy are ongoing.

Bismuth-213 for Targeted Radionuclide Therapy: From Atom to Bedside.

In contrast to external high energy photon or proton therapy, targeted radionuclide therapy (TRNT) is a systemic cancer treatment allowing targeted irradiation of a primary tumor and all its metastases, resulting in less collateral damage to normal tissues. The α-emitting radionuclide bismuth-213 (213Bi) has interesting properties and can be considered as a magic bullet for TRNT. The benefits and drawbacks of targeted alpha therapy with 213Bi are discussed in this review, covering the entire chain from radionuclide production to bedside. First, the radionuclide properties and production of 225Ac and its daughter 213Bi are discussed, followed by the fundamental chemical properties of bismuth. Next, an overview of available acyclic and macrocyclic bifunctional chelators for bismuth and general considerations for designing a 213Bi-radiopharmaceutical are provided. Finally, we provide an overview of preclinical and clinical studies involving 213Bi-radiopharmaceuticals, as well as the future perspectives of this promising cancer treatment option.

Improved antiparasitic activity by incorporation of organosilane entities into half-sandwich ruthenium(II) and rhodium(III) thiosemicarbazone complexes.

A series of ferrocenyl- and aryl-functionalised organosilane thiosemicarbazone compounds was obtained via a nucleophilic substitution reaction with an amine-terminated organosilane. The thiosemicarbazone (TSC) ligands were further reacted with either a ruthenium dimer [(η(6-i)PrC6H4Me)Ru(µ-Cl)Cl]2 or a rhodium dimer [(Cp*)Rh(µ-Cl)Cl]2 to yield a series of cationic mono- and binuclear complexes. The thiosemicarbazone ligands, as well as their metal complexes, were characterised using NMR and IR spectroscopy, and mass spectrometry. The molecular structure of the binuclear ruthenium(ii) complex was determined by single-crystal X-ray diffraction analysis. The thiosemicarbazones and their complexes were evaluated for their in vitro antiplasmodial activities against the chloroquine-sensitive (NF54) and chloroquine-resistant (Dd2) Plasmodium falciparum strains, displaying activities in the low micromolar range. Selected compounds were screened for potential ß-haematin inhibition activity, and it was found that two Rh(iii) complexes exhibited moderate to good inhibition. Furthermore, the compounds were screened for their antitrichomonal activities against the G3 Trichomonas vaginalis strain, revealing a higher percentage of growth inhibition for the ruthenium and rhodium complexes over their corresponding ligand.

trans-Dichloridobis[dicyclo-hex-yl(phen-yl)phosphane-κP]palladium(II).

The title compound, [PdCl(2){P(C(6)H(11))(2)(C(6)H(5))}(2)], forms a monomeric complex with a trans-square-planar geometry. The Pd-P bond lengths are 2.3343 (5) Å, as the Pd atom lies on an inversion centre, while the Pd-Cl bond lengths are 2.3017 (4) Å. The observed structure was found to be closely related to [PdCl(2){P(C(6)H(11))(3)}(2)] [Grushin et al. (1994 ▶). Inorg. Chem.33, 4804-4806], [PdBr(2){P(C(6)H(11))(3)}(2)] [Clarke et al. (2003 ▶). Dalton Trans. pp. 4393-4394] and [PdCl(2)P(C(6)H(11))(2)(C(7)H(7))}(2)] [Vuoti et al. (2008 ▶). Eur. J. Inorg. Chem. pp. 397-407] (C(6)H(11) is cyclo-hexyl and C(7)H(7) is o-tol-yl). One of the cyclo-hexyl rings is disordered with the phenyl ring in a 0.587 (9):413 (9) ratio. Five long-range C-H⋯Cl inter-actions were observed within the structure.

trans-Dichloridobis[diphen-yl(thio-phen-2-yl)phosphane-κP]palladium(II).

The title compound, trans-[PdCl(2)(C(16)H(13)PS)(2)], forms a monomeric complex with a trans-square-planar geometry. The Pd-P bond lengths are 2.3387 (11) Å, as the Pd atom lies on an inversion point, while the Pd-Cl bond lengths are 2.2950 (12) Å.

Triethyl-ammonium hexa-µ(2)-acetato-κO:O'-diacetato-κO-aqua-µ(3)-oxido-triferrate(III) toluene monosolvate.

The title compound, (C(6)H(16)N)[Fe(3)(CH(3)CO(2))(8)O(H(2)O)]·C(7)H(8), was serendipitously crystallized from a reaction of disilanol with iron(II) acetate. The trinuclear acetatoferrate(III) anion has a triethyl-ammonium cation as the counterion. The three Fe atoms lie on the vertices of a regular triangle and are octa-hedrally coordinated. The complete coordination of the anion includes shared ligands among the three metal ions: a central tribridging O atom and six bidentate bridging acetyl groups. The six-coordinations of two of the metal ions are completed by a monodentate acetate ligand, whereas that of the third metal ion is completed by a water mol-ecule. The uncoordinated triethyl-ammonium cation is involved in N-H⋯O hydrogen bonding to a singly coordinated acetyl group. The coordinated aqua mol-ecule is involved in bifurcated O-H⋯O hydrogen bonding. C-H⋯O inter-actions are also observed. The toluene solvent molecule is disordered over two sets of sites in a 0.609 (11):0.391 (11) ratio.

Bis(dicyclo-hexyl-phenyl-phosphine)silver(I) nitrate.

The title compound, [Ag(C(18)H(27)P)(2)]NO(3), is a mononuclear salt species in which the Ag atom is coordinated by two phosphine ligands, forming a cation, with the nitrate as the counter-anion, weakly inter-acting with the Ag atom, resulting in Ag⋯O distances of 2.602 (6) and 2.679 (6) Å. The cationic silver-phosphine complex has a non-linear geometry in which the P-Ag-P angle is 154.662 (19)°. The Ag-P bond lengths are 2.4303 (6) and 2.4046 (5) Å.

trans-Carbonyl-chloridobis[tris-(4-chloro-phen-yl)phosphane]rhodium(I) acetone monosolvate.

The title compound, trans-[RhCl(C(18)H(12)Cl(3)P)(2)(CO)]·C(3)H(6)O, contains an Rh(I) atom in a distorted square-planar coordination with a P-Rh-P angle of 175.27 (2)° and Rh-P bond lengths of 2.3127 (4) and 2.3219 (4) Å. The rhodium complexes link each other through weak inter-molecular contacts between the acetone methyl groups and the carbonyl O atom. Inter-actions between the acetone solvent mol-ecule and the Cl-Rh unit results in a reduced P-Rh-Cl angle of 86.675 (15)°.