Intramolecular Alkyne-de Mayo Reaction Using the Enol Methylene Acetal Linker: Experimental Implementation and Computational Simulation.

The enol-linked intramolecular alkyne-de Mayo reaction is a photochemically triggered cascade reaction suitable for the synthesis of substituted dihydrotropones by two-carbon ring expansion of enol ethers of cyclopentane-1,3-dion. We report on the implementation of the methylene acetal linker and the isolation of the initial (2 + 2) photocycloadduct in substances. We have investigated in depth the modus operandi of the ring-opening of the π-donor-π-acceptor cyclobutene derivatives by computational chemistry.

CycloSiFA: The Next Generation of Silicon-Based Fluoride Acceptors for Positron Emission Tomography (PET).

The ring-opening Si-fluorination of a variety of azasilole derivatives cyclo-1-(iPr2 Si)-4-X-C6 H3 -2-CH2 NR (4: R=2,6-iPr2 C6 H3 , X=H; 4 a: R=2,4,6-Me3 C6 H2 , X=H; 9: R=2,6-iPr2 C6 H3 , X=tBuMe2 SiO; 10: R=2,6-iPr2 C6 H3 , X=OH; 13: R=2,6-iPr2 C6 H3 , X=HCCCH2 O; 22: R=2,6-iPr2 C6 H3 , X=tBuMe2 SiCH2 O) with different 19 F-fluoride sources was studied, optimized and the experience gained was used in a translational approach to create a straightforward 18 F-labelling protocol for the azasilole derivatives [18 F]6 and [18 F]14. The latter constitutes a potential clickable CycloSiFA prosthetic group which might be used in PET tracer development using Cu-catalysed triazole formation. Based on our findings, CycloSiFA has the potential to become a new entry into non-canonical labelling methodologies for radioactive PET tracer development.

One-step ¹8F-labeling of carbohydrate-conjugated octreotate-derivatives containing a silicon-fluoride-acceptor (SiFA): in vitro and in vivo evaluation as tumor imaging agents for positron emission tomography (PET).

The synthesis, radiolabeling, and initial evaluation of new silicon-fluoride acceptor (SiFA) derivatized octreotate derivatives is reported. So far, the main drawback of the SiFA technology for the synthesis of PET-radiotracers is the high lipophilicity of the resulting radiopharmaceutical. Consequently, we synthesized new SiFA-octreotate analogues derivatized with Fmoc-NH-PEG-COOH, Fmoc-Asn(Ac3AcNH-ß-Glc)-OH, and SiFA-aldehyde (SIFA-A). The substances could be labeled in high yields (38 ± 4%) and specific activities between 29 and 56 GBq/µmol in short synthesis times of less than 30 min (e.o.b.). The in vitro evaluation of the synthesized conjugates displayed a sst2 receptor affinity (IC50 = 3.3 ± 0.3 nM) comparable to that of somatostatin-28. As a measure of lipophilicity of the conjugates, the log P(ow) was determined and found to be 0.96 for SiFA-Asn(AcNH-ß-Glc)-PEG-Tyr³-octreotate and 1.23 for SiFA-Asn(AcNH-ß-Glc)-Tyr³-octreotate, which is considerably lower than for SiFA-Tyr³-octreotate (log P(ow) = 1.59). The initial in vivo evaluation of [¹8F]SiFA-Asn(AcNH-ß-Glc)-PEG-Tyr³-octreotate revealed a significant uptake of radiotracer in the tumor tissue of AR42J tumor-bearing nude mice of 7.7% ID/g tissue weight. These results show that the high lipophilicity of the SiFA moiety can be compensated by applying hydrophilic moieties. Using this approach, a tumor-affine SiFA-containing peptide could successfully be used for receptor imaging for the first time in this proof of concept study.

Bis{deca-carbonyl-bis-[µ-2,2'-(phenyl-imino)-diethano-lato]ditin(II)ditungsten(0)(2 Sn-W)} hexa-carbonyl-tungsten(0).

In the title 2:1 adduct, [Sn(2)W(2)(C(10)H(13)NO(2))(2)(CO)(10)](2)[W(CO)(6)], the complete hexa-carbonyl-tungsten mol-ecule is generated by a crystallographic inversion centre. The heterometallic mol-ecule features a central Sn(2)O(2) core with essentially equal Sn-O(eth-oxy) bond lengths. The second eth-oxy O and amine N atoms of each N,O,O'-tridentate ligand coordinate to one Sn atom only. The NO(3) donor atoms occupy basal positions and the W atom the apical position in a distorted square-pyramidal geometry for each Sn atom. The W atoms are approximately syn to each other but the central metal core is non-planar [W-Sn⋯Sn-W pseudo-torsion angle = 43.573 (16)°]. One of the carbonyl ligands in the heterometallic mol-ecule is disordered over two orientations with equal occupancies. In the crystal, the heterometallic mol-ecules associate via C-H⋯O inter-actions, forming supra-molecular layers with undulating topology in the ab plane. These stack along the c axis, defining voids which are occupied by the W(CO)(6) mol-ecules.

[18F]SiFA-isothiocyanate: a new highly effective radioactive labeling agent for lysine-containing proteins.

A highly efficient (18)F-labeling synthon for universal protein labeling is reported. Diverse (18)F-labeled proteins of 66-144 kDa were prepared with [(18)F]SiFA-isothiocyanate synthesized by an isotopic (19)F for (18)F exchange at the silicon atom. Overall preparative radiochemical yields were 20-40 % after 40-50 min. No bone uptake of (18)F radioactivity was detected until 90 min post-injection of (18)F-SiFA-RSA; this demonstrates the metabolic stability of the [(18)F]SiFA moiety.

Kit-like 18F-labeling of proteins: synthesis of 4-(di-tert-butyl[18F]fluorosilyl)benzenethiol (Si[18F]FA-SH) labeled rat serum albumin for blood pool imaging with PET.

Radiosyntheses of 18F-radiopharmaceuticals for positron emission tomography (PET) normally require an extraordinarily high effort of technical equipment and specially trained personnel. We recently reported a novel method for the introduction of fluorine-18 into peptides for PET-imaging based on silicon-18F-chemistry (SiFA technique). We herewith introduce the first SiFA-based Kit-like radio-fluorination of a protein (rat serum albumin,RSA) and demonstrate its usefulness for in vivo imaging with microPET in normal rats as well as in a rat heterotropic transplanted heart model. As a labeling agent, we prepared 4-(di-tert-butyl[18F]fluorosilyl)benzenethiol (Si[18F]FASH)by simple isotopic exchange in 40-60% radiochemical yield (RCY) and coupled it directly to a Sulfo-SMCC derivatized RSA in an overall RCY of 12% within 20-30 min. The technically simple labeling procedure does not require any elaborated purification procedures and is a straightforward example of a successful application of Si-18F chemistry for in vivo imaging with PET.

para-Functionalized aryl-di-tert-butylfluorosilanes as potential labeling synthons for (18)F radiopharmaceuticals.

Broad spectrum: Novel para-functionalized aryl-di-tert-butylfluorosilanes, p-(tBu(2)FSi)C(6)H(4)X (X=functional group), have been made available and broaden the spectrum of silicon-based (18)F acceptors (SiFAs) for potential PET applications. For example, the [(18)F]maleimido derivative 1 has been employed for the synthesis of [(18)F]1- labeled rat serum albumin (RSA), the applicability of which for PET has been verified by in vivo experiments.The syntheses of the functionalized triorganofluorosilanes tBu(2)(p-XC(6)H(4))SiF (3 a, X=SH; 4 a, X=NCS; 4 b, X=NCO; 5, X=NC(4)H(2)O(2); 7, X=COOH; 8 a, X=COONC(4)H(4)O(2); 8 b, X=COOC(6)F(5)) are reported. These compounds display potential as silicon-based fluoride acceptors (SiFAs). The molecular structures of compounds 5, 7, and 8 a have been determined by single-crystal X-ray diffraction studies. With the exception of compounds 8 a and 8 b, all of the compounds could be (18)F-labeled by isotopic exchange in good to high radiochemical yields (RCY) with good to excellent specific activities. As proof of applicability, the maleimido-functionalized SiFA derivative 5, which is specific for thiol groups, has been used for the labeling of rat serum albumin (RSA) that had been derivatized with 2-iminothiolane. The incorporation of [(18)F]5 into the derivatized RSA reached a maximum yield after 30 min at ambient temperature. After purification, the [(18)F]RSA was evaluated in a healthy rat by means of muPET and displayed an expedient in vivo stability over 180 min.