Studies toward the Development of New Silicon-Containing Building Blocks for the Direct ¹⁸F-Labeling of Peptides

Abstract

Silicon-containing prosthetic groups have been conjugated to peptides to allow for a single-step labeling with (18)F radioisotope. The fairly lipophilic di-tert-butylphenylsilane building block contributes unfavorably to the pharmacokinetic profile of bombesin conjugates. In this article, theoretical and experimental studies toward the development of more hydrophilic silicon-based building blocks are presented. Density functional theory calculations were used to predict the hydrolytic stability of di-tert-butylfluorosilanes 2-23 with the aim to improve the in vivo properties of (18)F-labeled silicon-containing biomolecules. As a further step toward improving the pharmacokinetic profile, hydrophilic linkers were introduced between the lipophilic di-tert-butylphenylsilane building block and the bombesin congeners. Increased tumor uptake was shown with two of these peptides in xenograft-bearing mice using positron emission tomography and biodistribution studies. The introduction of a hydrophilic linker is thus a viable approach to improve the tumor uptake of (18)F-labeled silicon-bombesin conjugates.

Alkali Metal-Hydroxide-Catalyzed C(sp)–H Bond silylation

“…18 The bulky di-tert-butylsilane could also be introduced for the first time by catalytic C-H silylation yielding 2f in excellent yield, providing a point of entry into novel alkynylsilyl [ 18 F]PET radiopharmaceutical moieties. 12 Using Me3Si-SiHMe2 as a polysilane model compound and subjecting it to our cross-dehydrogenative silylation at ambient temperature gave 2l in 95% yield, providing a new synthetic strategy for the construction of advanced polysilane materials. 19 To the best of our knowledge, this is the most diverse scope of hydrosilanes reported to date for any single catalytic C-H silylation system.…”

In Vivo Evaluation of 18F-SiFAlin–Modified TATE: A Potential Challenge for 68Ga-DOTATATE, the Clinical Gold Standard for Somatostatin Receptor Imaging with PET

“…One of these approaches takes advantage of the thermodynamically favored formation of silicon-18 F bonds (silicon-fluoride acceptor [SiFA] chemistry, Fig. 1) (17)(18)(19)(20)(21)(22)(23). However, in vitro and in vivo studies revealed inherent difficulties for its in vivo applicability: the unalterably high lipophilicity of the silicon-containing building block necessary for the in vivo stability of the Si- 18 F bond leads to changes in the pharmacokinetic properties of the accordingly derivatized peptides (19,24).…”

Next Generation of SiFAlin-Based TATE Derivatives for PET Imaging of SSTR-Positive Tumors: Influence of Molecular Design on In Vitro SSTR Binding and In Vivo Pharmacokinetics

“…has attracted high attention due to the strong nature of the Si-18 F bond and more important its fast and efficient 18 Fradiolabeling as well as the simple product workup, enabling a kit-like synthesis of 18 Flabeled peptides. [19][20][21][22][23][24][25] Its characteristics such as the simple one-step 19 F-18 F-isotopic exchange reaction under very mild labeling conditions (5 min at ambient temperature) producing no side-products, the small precursor amounts (nmol range) required as well as high achievable radiochemical yields and specific activities of the obtained radiolabeled compounds illustrate the advantages of this 18 F-labeling chemistry. However, a structural prerequisite for a high hydrolytic stability of the 18 F-Si bond are the aromatic and two tert-butyl groups on the silicon atom ( Figure 1A), considerably increasing the overall lipophilicity of SiFA-modified substances.…”