Automated synthesis of 68 Ga/177 Lu-PSMA on the Trasis miniAllinOne.

Prostate-specific membrane antigen (PSMA)-based radioligands for positron emission tomography (PET)/computed tomography (CT) studies represent the gold standard for detection of recurrent prostate cancer (PCa). [68 Ga]PSMA-HBED-CC is a PET radiotracer suitable for detection of PCa, and its clinical use has become widespread over the last few years. In this contribution, we detail our GMP-compliant production of [68 Ga]PSMA-HBED-CC using the Trasis miniAllinOne radiosynthesizer and report synthetic and clinical data for the first 100 productions of 2019. Additionally, we detail our efforts towards a GMP-compliant production of the radiotherapeutic [177 Lu]PSMA-I&T using the same synthesis module. PSMA-based radioligand therapy (RLT) offers a possible future treatment in cases of metastatic castration-resistant PCa, and GMP-compliant routine production methods are therefore called for. This report highlights how PSMA-based agents for theranostic purposes can be conveniently produced at a single radiochemistry Good Manufacturing Practice (GMP) site, thereby facilitating optimized detection and treatment of PCa.

Importance of Axial Symmetry in Elucidating Lanthanide-Transition Metal Interactions.

In this paper, we experimentally study and model the electron donating character of an axial diamagnetic Pd2+ ion in four metalloligated lanthanide complexes of formula [PPh4][Ln{Pd(SAc)4}2] (SAc- = thioacetate, Ln = Tb, Dy, Ho, and Er). A global model encompassing inelastic neutron scattering, torque magnetometry, and dc magnetometry allows to precisely determine the energy level structure of the complexes. Solid state nuclear magnetic resonance reveals a less donating character of Pd2+ compared to the previously reported isostructural Pt2+-based complexes. Consequently, all complexes invariably show a lower crystal field strength compared to their Pt2+-analogues. The dynamic properties show an enhanced single molecule magnet behavior due to the suppression of quantum tunneling, in agreement with our model.

Molecular multifunctionality preservation upon surface deposition for a chiral single-molecule magnet.

The synthesis and characterization of a chiral, enneanuclear Mn(iii)-based, Single-Molecule Magnet, [Mn9O4(Me-sao)6(L)3(MeO)3(MeOH)3]Cl (1; Me-saoH2 = methylsalicylaldoxime, HL = lipoic acid) is reported. Compound 1 crystallizes in the orthorhombic P212121 space group and consists of a metallic skeleton describing a defect super-tetrahedron missing one vertex. The chirality of the [MnIII 9] core originates from the directional bridging of the Me-sao2- ligands via the -N-O- oximate moieties, which define a clockwise (1ΔΔ) or counter-clockwise (1ΛΛ) rotation in both the upper [MnIII 3] and lower [MnIII 6] subunits. Structural integrity and retention of chirality upon dissolution and upon deposition on (a) gold nanoparticles, 1@AuNPs, (b) transparent Au(111) surfaces, 1ΛΛ@t-Au(111); 1ΔΔ@t-Au(111), and (c) epitaxial Au(111) on mica surfaces, 1@e-Au(111), was confirmed by CD and IR spectroscopies, mass spectrometry, TEM, XPS, XAS, and AFM. Magnetic susceptibility and magnetization measurements demonstrate the simultaneous retention of SMM behaviour and optical activity, from the solid state, via dissolution, to the surface deposited species.

Chemical tunnel-splitting-engineering in a dysprosium-based molecular nanomagnet.

Total control over the electronic spin relaxation in molecular nanomagnets is the ultimate goal in the design of new molecules with evermore realizable applications in spin-based devices. For single-ion lanthanide systems, with strong spin-orbit coupling, the potential applications are linked to the energetic structure of the crystal field levels and quantum tunneling within the ground state. Structural engineering of the timescale of these tunneling events via appropriate design of crystal fields represents a fundamental challenge for the synthetic chemist, since tunnel splittings are expected to be suppressed by crystal field environments with sufficiently high-order symmetry. Here, we report the long missing study of the effect of a non-linear (C4) to pseudo-linear (D4d) change in crystal field symmetry in an otherwise chemically unaltered dysprosium complex. From a purely experimental study of crystal field levels and electronic spin dynamics at milliKelvin temperatures, we demonstrate the ensuing threefold reduction of the tunnel splitting.

Lanthanide coordination complexes framed by sodium ions: slow relaxation of the magnetization in the Dy(III) derivative.

Using a new polydentate Schiff-base ligand (H3L) we isolated three new tetranuclear isostructural lanthanide complexes with the general formula [LnNa2(L)4(DMF)4(H2O)2(AcO)2]·4DMF·2H2O [Ln = Dy (1), Ho (2), or Er (3)]. The structural characterization of the complexes reveals that the Na+ ions are coordinated in the structure which gives them a structure-directing role in the molecule. The magnetic behavior of the systems was investigated by means of SQUID magnetometry which revealed that complex 1 exhibits single molecule magnet behavior at low temperatures which is enhanced by the application of a 2000 Oe static magnetic field. We were able to extract an effective barrier of Ueff = 43(1) K, however, we show that the consideration of an Orbach relaxation mechanism being the dominant is not always correct for lanthanides. On the contrary, we elaborate how in this system the relaxation is caused by a combination of a direct and a Raman process.

Imposing high-symmetry and tuneable geometry on lanthanide centres with chelating Pt and Pd metalloligands.

Exploitation of HSAB preferences allows for high-yield, one-pot syntheses of lanthanide complexes chelated by two Pd or Pt metalloligands, [MII(SAc)4]2- (SAc- = thioacetate, M = Pd, Pt). The resulting complexes with 8 oxygen donors surrounding the lanthanides can be isolated in crystallographically tetragonal environments as either [NEt4]+ (space group: P4/mcc) or [PPh4]+ (space group: P4/n) salts. In the case of M = Pt, the complete series of lanthanide complexes has been structurally characterized as the [NEt4]+ salts (except for Ln = Pm), while the [PPh4]+ salts have been structurally characterized for Ln = Gd-Er, Y. For M = Pd, selected lanthanide complexes have been structurally characterized as both salts. The only significant structural difference between salts of the two counter ions is the resulting twist angle connecting tetragonal prismatic and tetragonal anti-prismatic configurations, with the [PPh4]+ salts approaching ideal D4d symmetry very closely (φ = 44.52-44.61°) while the [NEt4]+ salts exhibit intermediate twist angles in the interval φ = 17.28-27.41°, the twist increasing as the complete 4f series is traversed. Static magnetic properties for the latter half of the lanthanide series are found to agree well in the high temperature limit with the expected Curie behavior. Perpendicular and parallel mode EPR spectroscopy on randomly oriented powder samples and single crystals of the Gd complexes with respectively Pd- and Pt-based metalloligands demonstrate the nature of the platinum metal to strongly affect the spectra. Consistent parametrization of all of the EPR spectra reveals the main difference to stem from a large difference in the magnitude of the leading axial term, B02, this being almost four times larger for the Pt-based complexes as compared to the Pd analogues, indicating a direct Pt(5d z2 )-Ln interaction and an arguable coordination number of 10 rather than 8. The parametrization of the EPR spectra also confirms that off-diagonal operators are associated with non-zero parameters for the [NEt4]+ salts, while only contributing minimally for the [PPh4]+ salts in which lanthanide coordination approximates D4d point group symmetry closely.

Impact of TGF-ß inhibition during acute exercise on Achilles tendon extracellular matrix.

The purpose of this study was to evaluate the role of TGF-ß1 in regulating tendon extracellular matrix after acute exercise. Wistar rats exercised (n = 15) on a treadmill for four consecutive days (60 min/day) or maintained normal cage activity. After each exercise bout, the peritendinous space of each Achilles tendon was injected with a TGF-ß1 receptor inhibitor or sham. Independent of group, tendons injected with inhibitor exhibited ~50% lower Smad 3 (Ser423/425) (P < 0.05) and 2.5-fold greater ERK1/2 phosphorylation (P < 0.05) when compared with sham (P < 0.05). Injection of the inhibitor did not alter collagen content in either group (P > 0.05). In exercised rats, hydroxylyslpyridinoline content and collagen III expression were lower (P < 0.05) in tendons injected with inhibitor when compared with sham. In nonexercised rats, collagen I and lysyl oxidase (LOX) expression was lower (P < 0.05) in tendons injected with inhibitor when compared with sham. Decorin expression was not altered by inhibitor in either group (P > 0.05). On the basis of evaluation of hematoxylin and eosin (H&E) stained cross sections, cell numbers were not altered by inhibitor treatment in either group (P > 0.05). Evaluation of H&E-stained sections revealed no effect of inhibitor on collagen fibril morphology. In contrast, scores for regional variation in cellularity decreased in exercised rats (P < 0.05). No differences in fiber arrangement, structure, and nuclei form were noted in either group (P > 0.05). Our findings suggest that TGF-ß1 signaling is necessary for the regulation of tendon cross-link formation, as well as collagen and LOX gene transcription in an exercise-dependent manner.

Influence of acute and chronic streptozotocin-induced diabetes on the rat tendon extracellular matrix and mechanical properties.

Diabetes is a major risk factor for tendinopathy, and tendon abnormalities are common in diabetic patients. The purpose of the present study was to evaluate the effect of streptozotocin (60 mg/kg)-induced diabetes and insulin therapy on tendon mechanical and cellular properties. Sprague-Dawley rats (n = 40) were divided into the following four groups: nondiabetic (control), 1 wk of diabetes (acute), 10 wk of diabetes (chronic), and 10 wk of diabetes with insulin treatment (insulin). After 10 wk, Achilles tendon and tail fascicle mechanical properties were similar between groups (P > 0.05). Cell density in the Achilles tendon was greater in the chronic group compared with the control and acute groups (control group: 7.8 ± 0.5 cells/100 µm(2), acute group: 8.3 ± 0.4 cells/100 µm(2), chronic group: 10.9 ± 0.9 cells/100 µm(2), and insulin group: 9.2 ± 0.8 cells/100 µm(2), P < 0.05). The density of proliferating cells in the Achilles tendon was greater in the chronic group compared with all other groups (control group: 0.025 ± 0.009 cells/100 µm(2), acute group: 0.019 ± 0.005 cells/100 µm(2), chronic group: 0.067 ± 0.015, and insulin group: 0.004 ± 0.004 cells/100 µm(2), P < 0.05). Patellar tendon collagen content was ∼32% greater in the chronic and acute groups compared with the control or insulin groups (control group: 681 ± 63 µg collagen/mg dry wt, acute group: 938 ± 21 µg collagen/mg dry wt, chronic: 951 ± 52 µg collagen/mg dry wt, and insulin group: 596 ± 84 µg collagen/mg dry wt, P < 0.05). In contrast, patellar tendon hydroxylysyl pyridinoline cross linking and collagen fibril organization were unchanged by diabetes or insulin (P > 0.05). Our findings suggest that 10 wk of streptozotocin-induced diabetes does not alter rat tendon mechanical properties even with an increase in collagen content. Future studies could attempt to further address the mechanisms contributing to the increase in tendon problems noted in diabetic patients, especially since our data suggest that hyperglycemia per se does not alter tendon mechanical properties.

Design of Single-Molecule Magnets: Insufficiency of the Anisotropy Barrier as the Sole Criterion.

Determination of the electronic energy spectrum of a trigonal-symmetry mononuclear Yb(3+) single-molecule magnet (SMM) by high-resolution absorption and luminescence spectroscopies reveals that the first excited electronic doublet is placed nearly 500 cm(-1) above the ground one. Fitting of the paramagnetic relaxation times of this SMM to a thermally activated (Orbach) model {τ = τ0 × exp[ΔOrbach/(kBT)]} affords an activation barrier, ΔOrbach, of only 38 cm(-1). This result is incompatible with the spectroscopic observations. Thus, we unambiguously demonstrate, solely on the basis of experimental data, that Orbach relaxation cannot a priori be considered as the main mechanism determining the spin dynamics of SMMs. This study highlights the fact that the general synthetic approach of optimizing SMM behavior by maximization of the anisotropy barrier, intimately linked to the ligand field, as the sole parameter to be tuned, is insufficient because of the complete neglect of the interaction of the magnetic moment of the molecule with its environment. The Orbach mechanism is expected dominant only in the cases in which the energy of the excited ligand field state is below the Debye temperature, which is typically low for molecular crystals and, thus, prevents the use of the anisotropy barrier as a design criterion for the realization of high-temperature SMMs. Therefore, consideration of additional design criteria that address the presence of alternative relaxation processes beyond the traditional double-well picture is required.

Magnetic and magnetocaloric properties of an unusual family of carbonate-panelled [Ln(III)(6)Zn(III)(2)] cages.

The reaction of the pro-ligand H4L, which combines the complementary phenolic oxime and diethanolamine moieties within the same organic framework, with Zn(NO3)2·6H2O and Ln(NO3)3·6H2O in a basic methanolic solution generates a family of isostructural heterometallic coordination compounds of general formula [Ln6Zn2(CO3)5(OH)(H2L)4(H3L)2(H4L)]NO3·xMeOH [Ln = Gd, x = 30 (), Ln = Dy, x = 32 (), Ln = Sm, x = 31 (), Ln = Eu, x = 29 (), Ln = Tb, x = 30 ()]. The octametallic skeleton of the cage describes a heavily distorted [Gd] octahedron capped on two faces by Zn(II) ions. The metal core is stabilised by a series of µ3- and µ4-CO3(2-) ions, originating from the serendipitous fixation of atmospheric CO2. The magnetic properties of all family members were examined via SQUID magnetometry, with the χMT product and VTVB data of the Gd analogue () being independently fitted by numerical diagonalisation to afford the same best-fit parameter JGd-Gd = -0.004 cm(-1). The MCE of complex was elucidated from specific heat data, with the magnetic entropy change reaching a value of 22.6 J kg(-1) K(-1) at T = 1.7 K, close to the maximum entropy value per mole expected from six Gd(III) spins (SGd = 7/2), 23.7 J kg(-1) K(-1).

[ReF(6)](2-) : a robust module for the design of molecule-based magnetic materials.

A facile synthesis of the [ReF6 ](2-) ion and its use as a building block to synthesize magnetic systems are reported. Using dc and ac magnetic susceptibility measurements, INS and EPR spectroscopies, the magnetic properties of the isolated [ReF6 ](2-) unit in (PPh4 )2 [ReF6 ]⋅2 H2 O (1) have been fully studied including the slow relaxation of the magnetization observed below ca. 4 K. This slow dynamic is preserved for the one-dimensional coordination polymer [Zn(viz)4 (ReF6 )]∞ (2, viz=1-vinylimidazole), demonstrating the irrelevance of low symmetry for such magnetization dynamics in systems with easy-plane-type anisotropy. The ability of fluoride to mediate significant exchange interactions is exemplified by the isostructural [Ni(viz)4 (ReF6 )]∞ (3) analogue in which the ferromagnetic Ni(II) -Re(IV) interaction (+10.8 cm(-1) ) dwarfs the coupling present in related cyanide-bridged systems. These results reveal [ReF6 ](2-) to be an unique new module for the design of molecule-based magnetic materials.