Stereoselective ¹¹C Labeling of a “Native” Tetrapeptide by Using Asymmetric Phase‐Transfer Catalyzed Alkylation Reactions

Abstract

The first 11C‐labeled unmodified (“native”) peptide is described by alkylation of a tetrapeptide Schiff base, which was achieved by an automated five‐step radiochemical reaction. In a proof‐of‐concept study, [11C]Phe‐d‐Trp‐Lys‐Thr was synthesized. This tetrapeptide is the essential pharmacophore of octreotide, an antagonist of somatostatin receptors. The asymmetric alkylation with chiral phase‐transfer catalysts enabled direct labeling of a variety of isolated 11C‐peptides in a highly stereoselective manner (94 % de) with acceptable radiochemical yields (9–10 %) and practical specific activities (15–35 GBq µmol–1 or 405–945 mCi µmol–1) at the end of synthesis. This novel methodology provides a powerful new radiosynthetic method to access novel, stereochemically pure carbon‐11‐labeled native small peptides ready for in vivo studies.

From Carbon-11-Labeled Amino Acids to Peptides in Positron Emission Tomography: the Synthesis and Clinical Application

“…4b) with a diastereomeric excess of 94 % with d.c. RCY of 9-10 % and A M of 15-35 GBq μmol −1 in less than 60 min [87].…”

“…This methodology is comparable to the one described in the BRacemic and Asymmetric Synthesis with Schiff Base Precursor: N-(Diphenylmethylene) Glycine tertButyl Ester^section, where an N-terminal Schiff base peptide precursor was alkylated at the α-carbon, potentially in a stereoselective manner. Pekošak et al described the first C-11-labeled peptides and afforded multiple tetrapeptides [87] employing chiral phase-transfer catalysts in a reliable RCC and high diastereoselectiviy, as depicted in Fig. 10b and discussed in more detail below in the BCarbon-11-Labeled Somatostatin or Octreotate Analogues^section.…”

“…Many somatostain analogues have been developed and analyzed, whereas the radiolabeled analogue of the most well-known cyclic octapeptide-Octreotide-has become the gold standard for neuroendocrine tumors. Driven by the success of Octreotide and the significant potential of a large number of C-11 PET radiopharmaceuticals in clinical application, several C-11 somatostatin/octreotide analogues have been developed [1,87,94].…”

Efficient Synthesis of 11C‐Acrylesters, 11C‐Acrylamides and Their Application in Michael Addition Reactions for PET Tracer Development

“…[15] Generally, lower temperatures are favored in PTC reactions to enhance stereoselectivity. [18,27,28] This is presumably caused by the reaction time, since in carbon-11 radiosynthesis only rapid reactions can be considered because of the short half-life of 20 min, whereas in organic chemistry longer reaction times are feasible. Because of a solid-liquid phase reaction taking place, a sufficient interfacial area between the two phases needs to be created by vigorous stirring.…”

“…[9,10] Another advantage, when applying the second methodology is the low isotopic dilution when making use of [ 11 C]CO compared to [ 11 C]CO 2 , which in general yields higher A M . [18] In addition, the asymmetric Michael addition [19,20] has been explored in 12 C-organic chemistry; however, this challenging radiosynthesis method is unprecedented in radiochemistry thus far. [10,11] Moreover, nowadays also alternative procedures have been published to obtain [ 11 C]CO from [ 11 C]CO 2 using simplified and straightforward methodologies.…”