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

Abstract

Both the racemic and the stereoselective synthesis of the silicon‐modified amino acid p‐(tBu2FSi)C6H4CH2(NH2)COOH (SiFA‐phenylalanine, 6) and its derivatives p‐(tBu2FSi)C6H4CH2(NHBoc)COOH (10) and p‐(tBu2FSi)C6H4CH2(NHFmoc)COOH (11) are reported. The latter two compounds are valuable building blocks for the convenient introduction of silicon‐based fluoride acceptors (SiFAs) into peptides by solid‐phase peptide syntheses (SPPS). As prove of principle, the Tyr3‐octreotate derivatives 12, 13 and 14 were prepared by using standard protocols of the solid‐phase peptide synthesis (SPPS). They were labelled with 18F‐fluorine by isotopic exchange in radiochemical yields of up to 70 % (with radiochemical purity ranging between 92 and 99 %). The incorporation of 18F‐fluorine into the SiFA‐modified amino acid 6 was studied as the latter may also serve as a tracer in PET. After purification, [18F]‐6 showed a remarkable stability in an isotonic solution. Also reported is the molecular structure, as determined by single‐crystal X‐ray diffraction analysis, of p‐(tBu2FSi)C6H4CHCH[C(O)OMe]NHC(O)OCH2Ph (8), which serves as a precursor for the stereoselective synthesis of compound 6.

Three Methods for 18F Labeling of the HER2-Binding Affibody Molecule ZHER2:2891 Including Preclinical Assessment

“…With regard to the automation potential of the radiolabeling protocol, we also focused our attention on 2 simple 1-step methods. The silicon-fluoride acceptor approach ( 18 F-SiFA) by Schirrmacher et al with an isotopic 19 F/ 18 F exchange reaction by aqueous 18 F-fluoride appeared to be promising (23,24). As a third method, we studied the 18 F-AlF-NOTA concept developed by McBride et al (25)(26)(27)(28)(29).…”

A silicon‐labelled amino acid suitable for late‐stage fluorination and unexpected oxidative cleavage reactions in the preparation of a key intermediate in the Strecker synthesis

“…For instance, up to 90% conversion to the undesired benzaldehyde 8 was observed with excess PCC (4 equivalents) within 6 hr of reaction time at room temperature (Scheme , Entry 1). This result was curious given a previous report in which a similar aldehyde was prepared using chromium based oxidations under similar conditions without mention of this side reaction . Using two equivalents of PCC still resulted in a mixture of 2 and 8 , and using only one equivalent resulted in a mixture of aldehydes 2 and 8 , as well as unreacted alcohol 3 (Scheme , Entries 3–4).…”

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

“…At 37°C in plasma, half-lives of both compounds were below 5 min. We then refocused our efforts to the SiFA (Silicon-fluoride-acceptor) compounds developed by Schirrmacher et al [6][7][8][16][17][18][19][20][21][22][23] In this case, silicon is substituted by a phenyl and two t-butyl groups.…”

“…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.…”