Chiral nickel(ii) complexes in the preparation of¹¹C- and¹⁸F-labelled enantiomerically pure α-amino acids

Abstract

Positron emission tomography (PET) utilises positron emitting radiopharmaceuticals in the study of metabolic and physiological processes. FDG-PET is a useful technique for tumour detection; however FDG has disadvantages. The incorporation of labelled amino acids into brain tumours and into some other organs with high physiological consumption of glucose is a superior diagnostic method due to its much higher selectivity compared to FDG. A Ni(II) complex with a Schiff base of BPB and glycine was one of the first glycine synthons used for asymmetric synthesis of carbon-11 and fluorine-18 labelled α-amino acids. A similar complex was employed for routine preparation of [(18)F]FET. Physico-chemical investigations allowed us to design modified complexes with much stronger stereodiscriminative power including stereospecific ones. Chiral nickel complexes are also used for the preparation of tailored amino acids for the incorporation into peptides followed by labelling the peptides with fluorine-18 labelled "click" reagents. This review covers PET applications of Ni(II) complexes of Schiff base of BPB and α-amino acids from 1989 to date.

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

“…Furthermore, essential technical details, such as stirring, temperature control, and successive addition of chemicals, had to be fine-tuned as well. By adjusting the conditions, Bolster et al successfully synthesiezed [1- [27] and [1][2][3][4][5][6][7][8][9][10][11] C]MET [41,42] with RCP 9 94 % within 35 min, followed by chiral resolution to obtain the desired enantiomer as PET tracer in RCY of 10-15 %. [44], and is now used for PET imaging studies.…”

“…3a, a vast number of racemic [ 11 C]AAs have been described in literature, namely phenylalanine [26], ornithine and lysine [38], tyrosine [28,30], proline [39] and phenylglycine [26], and achiral glycine [25,26]. The [1][2][3][4][5][6][7][8][9][10][11] C]proline has been reported in 12-18 % RCY with a RCP of 9 95 % in total synthesis time of 45 min [39].…”

“…Thereafter, this strategy was followed to radiolabel a wide range of other racemic [3][4][5][6][7][8][9][10][11] C]AAs, namely alanine, 2-aminobutyric acid, norvaline, norleucine, and leucine [46]. All these reactions employed phase-transfer alkylation conditions using achiral catalyst tetrabutylammonium hydrogen sulfate and the achiral precursor, N-(diphenylmethylene) glycine tert-butyl ester, with different ]AA, removal of the protecting group of the alkylated intermediate, occurred in 5 min at 130°C using strong acidic conditions (e.g., concentrated HCl).…”

“…Carbon-11 Amino Acid Labeling of [1][2][3][4][5][6][7][8][9][10][11] C]Carboxyl-Function Bucherer-Strecker Synthesis The Strecker reaction, and its modified Bucherer-Strecker hydantoin synthesis, is one of the earliest one-pot and atom economic multi-component reactions for AA synthesis in general. The simplicity of the synthesis-simple mixing of the reagents acetaldehyde, ammonia (or amines) and hydrogen cyanide resulting in an α-aminonitrile adduct and its subsequent hydrolysis-has attracted radiochemists to synthesize [ 11 [29], whereas the second approach employed [ 11 C]CO 2 which reacted with α-lithiated precursor [30].…”

“…Additionally, the use of AAs as PET tracers often result in high contrast images which are not distorted by tissue inflammation, as is known for glucose-based PET tracer [ 18 F]FDG. The brain, heart, and inflamed areas use glucose as nutrient; therefore, these regions are difficult to distinguish from metastasis in [ 18 F]FDG PET studies [2,6,7]. The radionuclides used for PET to label natural and unnatural AAs include C-11 (t 1/2 20.4 min), N-13 (t 1/2 10.0 min), F-18 (t 1/2 1.8 h), and I-124 (t 1/2 4.2 days) [3].…”