para‐Functionalized Aryl‐di‐tert‐butylfluorosilanes as Potential Labeling Synthons for ¹⁸F Radiopharmaceuticals

Abstract

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.

SiFA‐Modified Phenylalanine: A Key Compound for the Efficient Synthesis of 18F‐Labelled Peptides

“…The Si(1)-F(1) dis- tance [1.614(4) Å] is rather similar to those in other SiFAmodified compounds. [7] A noteworthy feature is the asymmetric intramolecular N(17)-H···O (29) hydrogen bond that links two molecules of 8 into a dimer. Such hydrogen bonds are common for solid-state structures of p-silylarylcarboxylic acids and their derivatives.…”

“…Such hydrogen bonds are common for solid-state structures of p-silylarylcarboxylic acids and their derivatives. [7] Hydrogenation of compound 8 in the presence of a chiral Rh I catalyst gave the protected amino acid 9 with an ee of 98 % for the S-and 99 % for the R isomer, respectively. Deprotection took place in concentrated hydrobromic acid solution over a period of 15 min (Scheme 3).…”

“…[12] The known SiFA-aldehyde was prepared in good yield as described in our previous works [5,7] and treated with tetramethylguanidine and methyl-2-(benzyloxycarbonylamino)-2-(dimethoxy-phosphoryl)acetate in a Horner-Wadsworth-Emmons reaction to give compound 8 as a colourless solid (Scheme 3). Single crystals of 8 suitable for X-ray diffraction analysis were obtained by recrystallization from n-hexane.…”

“…[6] Consequently, the functionalized triorganofluorosilanes tBu 2 [p-XC 6 H 4 ]SiF were prepared as a silicon-based fluorine acceptor (SiFA) and linked, through the functionality X, to biomolecules; these were then successfully applied for evaluation in preclinical studies. [7] More recently, we and others described the in vivo application of tumour-affine peptides radiolabelled by the SiFA-approach in tumour-bearing mice. [2d,4d] In continuation of these studies, we report here the syntheses of SiFA-phenylalanine, the first SiFA-modified amino acid.…”

Synthesis of new 18F-radiolabeled silicon-based nitroimidazole compounds

“…Moreover, the stability towards hydrolysis of these new labeled fluorosilanes by comparison with the di-tert-butylphenylfluorosilane prosthetic groups (SiFA) described in the literature [16][17][18][19][20][21][22][23] (Fig. 2) will be discussed.…”