Direct Cu-mediated aromatic 18F-labeling of highly reactive tetrazines for pretargeted bioorthogonal PET imaging

Pretargeted imaging can be used to visualize and quantify slow-accumulating targeting vectors with short-lived radionuclides such as fluorine-18 – the most popular clinically applied Positron Emission Tomography (PET) radionuclide. Pretargeting results in higher target-to-background ratios compared to conventional imaging approaches using long-lived radionuclides. Currently, the tetrazine ligation is the most popular bioorthogonal reaction for pretargeted imaging, but a direct ¹⁸F-labeling strategy for highly reactive tetrazines, which would be highly beneficial if not essential for clinical translation, has thus far not been reported. In this work, a simple, scalable and reliable direct ¹⁸F-labeling procedure has been developed. We initially studied the applicability of different leaving groups and labeling methods to develop this procedure. The copper-mediated ¹⁸F-labeling exploiting stannane precursors showed the most promising results. This approach was then successfully applied to a set of tetrazines, including highly reactive H-tetrazines, suitable for pretargeted PET imaging. The labeling succeeded in radiochemical yields (RCYs) of up to approx. 25%. The new procedure was then applied to develop a pretargeting tetrazine-based imaging agent. The tracer was synthesized in a satisfactory RCY of ca. 10%, with a molar activity of 134 ± 22 GBq μmol⁻¹ and a radiochemical purity of >99%. Further evaluation showed that the tracer displayed favorable characteristics (target-to-background ratios and clearance) that may qualify it for future clinical translation.

A simple, scalable and reliable direct ¹⁸F-labeling procedure has been developed and applied to obtain a pretargeting tetrazine-based imaging agent with favorable in vivo characteristics.     

The crystal and molecular structure of a dinuclear copper(II) complex of a Robson-type macrocycle, [Cu2(C26H30N4O2)(H2O)2](BF4)2

Summary The crystal structure of the dinuclear complex [Cu₂(C₂₆H₃₀-N₄O₂)(H₂O)₂](BF₄)₂ was determined by x-ray crystallography. The crystals are triclinic, P¯1, witha = 10.945(5),b = 8.703(5),c = 8.495(5) Å, = 103.86(3)°, = 105.73(3)°, = 85.77(3)°, V = 756 ų D_c = 1.65 g cm^–3 for Z = 1. The copper(II) atoms are 5-coordinate and square-pyramidal. Selected bond distances are: Cu-N, 1.91 Å (mean); Cu-O(base) = 1.90(1) and 1.91(1) Å; Cu-O(apical) = 2.47(1) Å; There are O(water)-H ... F interionic hydrogen bonds in the structure. The Cu .. Cu distance is 2.847 Å.     

Intercalation of heterocyclic compounds in α-zirconium phosphate: Imidazole,benzimidazole, histamine and histidine

The intercalation of imidazole and some organic species containing the imidazole ring, between the layers of crystalline zirconium phosphate has been investigated. Fourteen new, well-ordered intercalation compounds are obtained with the batch procedure at r.t. and/or 60°C. A mechanism of formation of the various compounds is proposed on the basis of the interaction between the guest molecules (with their dimensions and geometries) and the free PO₃OH groups available between the layers of the host. The new phases have been characterized by TG and X-ray methods.     

Hierarchical Archimedean Dependence in Common Shock Models

Methodology and Computing in Applied Probability - In this paper we show how to extend a simple common shock model with Archimedean dependence of the hidden variables to the non-exchangeable case....     

New Results on Rational Approximation

Results in Mathematics - First asymptotic relations of Voronovskaya-type for rational operators of Shepard-type are shown. A positive answer in some senses to a problem on the pointwise...     

On a characterization of orthogonality with respect to particular sequences of random variables in <Emphasis Type="Italic">L</Emphasis><Superscript>2</Superscript>

This note deals with the orthogonality between sequences of random variables. The main idea of the note is to apply the results on equidistant systems of points in a Hilbert space to the case of the space L ²(Ω, F, ℙ) of real square integrable random variables. The main result gives a necessary and sufficient condition for a particular sequence of random variables (elements of which are taken from sets of equidistant elements of L ²(Ω, F, ℙ) to be orthogonal to some other sequence in L ²(Ω, F, ℙ). The result obtained is interesting from the point of view of the time series analysis, since it can be applied to a class of sequences random variables that exhibit a monotonically increasing variance. An application to ergodic theorem is also provided.     

Integral points, divisibility between values of polynomials and entire curves on surfaces

We prove some new degeneracy results for integral points and entire curves on surfaces; in particular, we provide the first examples, to our knowledge, of a simply connected smooth variety whose sets of integral points are never Zariski-dense. Some of our results are connected with divisibility problems, i.e. the problem of describing the integral points in the plane where the values of some given polynomials in two variables divide the values of other given polynomials.