Selection of the first 99m^{99m} Tc-Labelled somatostatin receptor subtype 2 antagonist for clinical translation : preclinical assessment of two optimized candidates

Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project “TECANT” two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [99mTc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [99mTc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [99mTc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, [99mTc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [99mTc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [99mTc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [99mTc]Tc-TECANT-1 for clinical translation of the first 99mTc-based SST2 antagonist

Author's personal copy Mobility of acidic protons in zeolites: A neutron diffraction study of D-heulandite

a b s t r a c t Neutron Rietveld refinement of a natural heulandite (Si/Al = 3.1) in its deuterium form was performed in space group C2/m. Two Brønsted acid sites were identified. One was on framework oxygen O1, occupied to 20% and headed toward the center of the 8-membered ring channel running parallel to [1 0 2]; the other was on O6, occupied to 30% and headed toward the 10-membered ring channel running parallel to the c-axis. Three other extraframework sites, located around a distance of 3 Å from the framework oxygens, were attributed to reabsorbed H 2 O molecules. On the whole, about 3.2 Brønsted acid sites were located representing about 37% of the value expected on the basis of the aluminium content. This discrepancy is attributed to proton transfer from th

Electron crystallography and dedicated electron-diffraction instrumentation

Electron diffraction (known also as ED, 3D ED or microED) is gaining momentum in science and industry. The application of electron diffraction in performing nano-crystallography on crystals smaller than 1 µm is a disruptive technology that is opening up fascinating new perspectives for a wide variety of compounds required in the fields of chemical, pharmaceutical and advanced materials research. Electron diffraction enables the characterization of solid compounds complementary to neutron, powder X-ray and single-crystal X-ray diffraction, as it has the unique capability to measure nanometre-sized crystals. The recent introduction of dedicated instrumentation to perform ED experiments is a key aspect of the continued growth and success of this technology. In addition to the ultra-high-speed hybrid-pixel detectors enabling ED data collection in continuous rotation mode, a high-precision goniometer and horizontal layout have been determined as essential features of an electron diffractometer, both of which are embodied in the Eldico ED-1. Four examples of data collected on an Eldico ED-1 are showcased to demonstrate the potential and advantages of a dedicated electron diffractometer, covering selected applications and challenges of electron diffraction: (i) multiple reciprocal lattices, (ii) absolute structure of a chiral compound, and (iii) R-values achieved by kinematic refinement comparable to X-ray data

"Off-axis" metal-metal bond in Mn2(CO)10 at high pressure

At variance with what was previously reported, Mn2(CO)10does not transform its conformation from staggered to eclipsed in the high pressure crystal form. X-ray powder diffraction, DFT calculations and Raman spectroscopy show that the staggered conformation is retained. Instead, a rotation and a translation of the Mn(CO)5pyramidal units produce an "off-axis" and rather shorter Mn-Mn bond. This journal i

Optimal scan time for evaluation of parathyroid adenoma with [18F]-fluorocholine PET/CT

Background. Parathyroid adenomas, the most common cause of primary hyperparathyroidism, are benign tumours which autonomously produce and secrete parathyroid hormone. [18F]-fluorocholine (FCH), PET marker of cellular proliferation, was recently demonstrated to accumulate in lesions representing enlarged parathyroid tissue; however, the optimal time to perform FCH PET/CT after FCH administration is not known. The aim of this study was to determine the optimal scan time of FCH PET/CT in patients with primary hyperparathyroidism

Thermal, Spectroscopic, and Ab Initio Structural Characterization of Carprofen Polymorphs

Commercial and recrystallized polycrystalline samples of carprofen, a nonsteroidal anti-inflammatory drug, were studied by thermal, spectroscopic, and structural techniques. Our investigations demonstrated that recrystallized sample, stable at room temperature (RT), is a single polymorphic form of carprofen (polymorph I) that undergoes an isostructural polymorphic transformation by heating (polymorph II). Polymorph II remains then metastable at ambient conditions. Commercial sample is instead a mixture of polymorphs I and II. The thermodynamic relationships between the two polymorphs were determined through the construction of an energy/temperature diagram. The ab initio structural determination performed on synchrotron X-Ray powder diffraction patterns recorded at RT on both polymorphs allowed us to elucidate, for the first time, their crystal structure. Both crystallize in the monoclinic space group type P21/c, and the unit cell similarity index and the volumetric isostructurality index indicate that the temperature-induced polymorphic transformation I→II is isostructural. Polymorphs I and II are conformational polymorphs, sharing a very similar hydrogen bond network, but with different conformation of the propanoic skeleton, which produces two different packing. The small conformational change agrees with the low value of transition enthalpy obtained by differential scanning calorimetry measurements and the small internal energy computed with density functional methods