Synthesis and evaluation of a [18F]fluorinated quaternary α-amino acid-based arginase inhibitor

dos Santos Clemente, G., F. Antunes, I., Kurhade, S., Dömling, A. & Elsinga, P. H., 15-May-2018, In : EJNMMI Radiopharmacy and Chemistry. 3, 7 (Suppl.1), p. 30-31

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Aim: Arginase catalyzes the hydrolysis of arginine to ornithine and urea, being the final enzyme of the urea cycle, which is a ubiquitous pathway to excrete toxic ammonia from organisms. Lately, it also has emerged as a key regulator of nitric oxide by competing with NO synthase for the same substrate. Therefore, arginase overexpression has been associated with a series of pathogenic processes that can go from cardiovascular, immune-mediated or inflammatory conditions to tumor cell metabolism.(1) Several research groups have been involved in the development of small-molecule arginase inhibitors reaching to data holding great promise. However, only recently the drug development industry is attaining clinical trials.(2)Since the association to PET labeling techniques has great relevance not only for the evaluation and characterization of some of this molecules, but also to increase the library of radiotracers available, our goal with this work was to synthesize and evaluate the [18F]fluorinated equivalent of a late-generation arginase inhibitor.(3)
Methods: An arylboronic acid pinacol ester-derived precursor was synthesized in view of a Cu-mediated nucleophilic [18F]fluorination. Radiochemical yield for the conversion of the intermediate species was assessed by TLC-SG and/or radioHPLC. Deprotection of the amino acid moiety was achieved by hydrolysis and the final radiotracer was purified by semi-preparative HPLC and obtained, after reformulation, as a physiological and injectable solution. Further stability and distribution-coefficient studies were performed.
Results: In summary, radiochemical yield of the conversion of the arylboronic ester-derived precursor reached ~80% when using 60 to 15 μmol (lower amounts brought significant losses in yield). Final [18F]fluorinated compound was obtained with radiochemical purity ≥95% in an overall yield of 11% (d.c., non-automated synthesis). The radiotracer showed stability in solution up to 4 h and an experimental log D of -0.67±0.05.
Conclusion: The [18F]fluorinated arginase inhibitor was efficiently labeled with fluorine-18 in good yield. Preliminary in vitro studies using R22v1 cell lines, which express Arg2, revealed a cellular uptake of the radiotracer susceptible of being blocked after treatment with arginase inhibitors. Further studies are currently being performed in different cell lines which either overexpress Arg1 or Arg2 to evaluate the potential of the developed radiotracer towards arginase mapping.
1. Caldwell RB, Toque HA, Narayanan SP, Caldwell RW, [2015], Trends Pharmacol Sci, 36(6):395-405
2. Pudlo M, Demougeot C, Girard-Thernier C, [2017], Med Res Rev, 37(3):475-513; (3) Van Zandt M, Golebiowski A, Ji MK, Whitehouse D, Ryder T, Beckett P, [2011], WO Patent 2011/133653A1.
Original languageEnglish
Pages (from-to)30-31
JournalEJNMMI Radiopharmacy and Chemistry
Issue number7 (Suppl.1)
Publication statusPublished - 15-May-2018
Event19th European Symposium
on Radiopharmacy and Radiopharmaceuticals
- Groningen, Netherlands
Duration: 5-Apr-20188-Apr-2018


19th European Symposium
on Radiopharmacy and Radiopharmaceuticals


Groningen, Netherlands

Event: Conference

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