Synlett 2017; 28(03): 371-375
DOI: 10.1055/s-0036-1588638
letter
© Georg Thieme Verlag Stuttgart · New York

High-Yielding Automated Convergent Synthesis of No-Carrier-Added [11C-Carbonyl]-Labeled Amino Acids Using the Strecker Reaction

Junhao Xing
a  Department of Radiology, University of Michigan Medical School, 2276 Med Sci I/SPC5610, 1301 Catherine St, Ann Arbor, MI 48109, USA   Email: xshao@umich.edu
b  Center of Drug Discovery, State Key Laboratory of Natural Medicines, Chinese Pharmaceutical University, 24 Tongjiaxiang, Nanjing 21009, P. R. of China
,
Allen F. Brooks
a  Department of Radiology, University of Michigan Medical School, 2276 Med Sci I/SPC5610, 1301 Catherine St, Ann Arbor, MI 48109, USA   Email: xshao@umich.edu
,
Dylan Fink
a  Department of Radiology, University of Michigan Medical School, 2276 Med Sci I/SPC5610, 1301 Catherine St, Ann Arbor, MI 48109, USA   Email: xshao@umich.edu
,
Huibin Zhang
b  Center of Drug Discovery, State Key Laboratory of Natural Medicines, Chinese Pharmaceutical University, 24 Tongjiaxiang, Nanjing 21009, P. R. of China
,
Morand R. Piert
a  Department of Radiology, University of Michigan Medical School, 2276 Med Sci I/SPC5610, 1301 Catherine St, Ann Arbor, MI 48109, USA   Email: xshao@umich.edu
,
Peter J. H. Scott
a  Department of Radiology, University of Michigan Medical School, 2276 Med Sci I/SPC5610, 1301 Catherine St, Ann Arbor, MI 48109, USA   Email: xshao@umich.edu
c  Interdepartmental Program in Medicinal Chemistry, University of Michigan, 428 Church St, Ann Arbor, MI 48109, USA
,
Xia Shao*
a  Department of Radiology, University of Michigan Medical School, 2276 Med Sci I/SPC5610, 1301 Catherine St, Ann Arbor, MI 48109, USA   Email: xshao@umich.edu
› Author Affiliations
Further Information

Publication History

Received: 11 August 2016

Accepted after revision: 10 October 2016

Publication Date:
07 November 2016 (online)


Abstract

A new variant of the Strecker synthesis using no-carrier-added [11C]cyanide for the synthesis of radiolabeled amino acids is described. The protocol is fully automated using a radiochemistry synthesis module and applied to the production of a number of new PET radiotracers. [11C-Carbonyl]sarcosine, [11C-carbonyl]methionine, [11C-carbonyl]-N-phenylglycine, and [11C-carbonyl]glycine are all synthesized in moderate to good radiochemical yields. The synthesis of [11C-carbonyl]sarcosine has been validated for production of doses for clinical use, and preliminary evaluation of the new radiotracer in PC3 tumor-bearing mice is also reported.

Supporting Information

 
  • References and Notes

    • 1a For an overview of PET imaging, see: Ametamey SM, Honer M, Schubiger PA. Chem. Rev. 2008; 108: 1501

    • For a general review of PET radiochemistry, see:
    • 1b Miller PW, Long NJ, Vilar R, Gee AD. Angew. Chem. Int. Ed. 2008; 47: 8998

      For an overview of the use of PET imaging in individualized healthcare, see:
    • 2a Pither R. Expert Rev. Mol. Diagn. 2003; 3: 703

    • For a review covering the use of PET in drug discovery, see:
    • 2b Matthews PM, Rabiner EA, Passchier J, Gunn RN. Br. J. Clin. Pharmacol. 2012; 73: 175

      For recent reviews on the use of radiolabeled amino acids in PET imaging, see:
    • 3a Galldiks N, Langen K.-J. Q. J. Nucl. Med. Mol. Imaging 2015; 59: 70
    • 3b Huang C, McConathy J. J. Nucl. Med. 2013; 54: 1007
    • 3c Jager PL, Vaalburg W, Pruim J, de Vries EG, Langen KJ, Piers DA. J. Nucl. Med. 2001; 42: 432
    • 4a Xing J, Brooks A, Scott P, Piert M, Shao X. J. Nucl. Med. 2016; 57: 1068; Suppl. 2
    • 4b Shao X, Rrajendiran T, Sherman P, Quesada C, Scott P, Chinnaiyan A, Piert M. J. Nucl. Med. 2014; 55: 1064 (Suppl. 1)
    • 5a Porter DH, Cook RJ, Wagner C. Arch. Biochem. Biophys. 1985; 243: 396
    • 5b Glorieux FH, Scriver CR, Delvin E, Mohyuddin F. J. Clin. Invest. 1971; 50: 2313
  • 6 Mossine AV, Brooks AF, Jackson IM, Quesada CA, Sherman P, Cole EL, Donnelly DJ, Scott PJ. H, Shao X. Bioconjugate Chem. 2016; 27: 1382

    • For recent reviews of CO2 fixation chemistry, see:
    • 7a Rotstein BH, Liang SH, Placzek MS, Hooker JM, Gee AD, Dollé F, Wilson AA, Vasdev N. Chem. Soc. Rev. 2016; 45: 4708
    • 7b Rotstein BH, Liang SL, Holland JP, Collier TL, Hooker JM, Wilson AA, Vasdev N. Chem. Commun. 2013; 49: 5621
  • 8 Strecker A. Ann. Chem. Pharm. 1850; 75: 27

    • For reviews of the Strecker reaction, including modern asymmetric variants, see:
    • 9a Cai X.-H, Xie B. ARKIVOC 2014; (i): 205
    • 9b Khan NH, Kureshy RI, Abdi SH. R, Bajaj HC, Sadhukhan A In Comprehensive Inorganic Chemistry II . Vol. 6. Reedijk J, Poeppelmeier K. Elsevier; Amsterdam: 2013: 413
    • 9c Wang J, Liu X, Feng X. Chem. Rev. 2011; 111: 6947
    • 9d Martens J. ChemCatChem 2010; 2: 379
    • 9e Sato K. Kendai Kagaku 2009; 465: 16
    • 9f Shibasaki M, Kanai M, Mita T. Org. React. 2008; 70: 1
    • 9g Galatsis P In Name Reactions for Functional Group Transformations . Li JJ, Corey EJ. John Wiley and Sons; Hoboken: 2007: 477
    • 9h Yet L. Angew. Chem. Int. Ed. 2001; 40: 875
    • 9i Enders D, Shilvock JP. Chem. Soc. Rev. 2000; 29: 359
    • 10a Cai H, Magner TJ, Muzik O, Wang M.-W, Chugani DC, Chugani HT. ACS Med. Chem. Lett. 2014; 5: 1152
    • 10b Kabalka GW, Nichols TL, Akula M, Longford CP. D, Miller L In Isotopically Labelled Compounds . Pleiss U, Voges R. John Wiley and Sons; Chichester: 2007. Vol. 7 329
    • 10c Drandarov K, Schubiger PA, Westera G. Appl. Radiat. Isot. 2006; 64: 1613
    • 10d Studenov AR, Szalda DE, Ding Y.-S. Nucl. Med. Biol. 2003; 30: 39
    • 10e Prenant C, Theobald A, Siegel T, Joachim J, Weber K, Haberkorn U, Oberdorfer F. J. Labelled Compd. Radiopharm. 1995; 36: 579
    • 10f Adam MJ, Grierson JR, Ruth TJ, Pedersen K, Pate BD. J. Nucl. Med. 1987; 28: 1599
    • 10g Johnström P, Stone-Elander S, Ericson K, Mosskin M, Bergström M. Appl. Radiat. Isot. 1987; 38: 729
    • 10h Halldin C, Schoeps K.-O, Stone-Elander S, Wiesel F.-A. Eur. J. Nucl. Med. 1987; 13: 288
    • 10i Halldin C, Långström B. J. Labelled Compd. Radiopharm. 1985; 22: 631
    • 10j Schmall B, Conti PS, Bigler RE, Zanzonico PB, Dahl JR, Sundoro-Wu BM, Jacobsen JK, Lee R. Int. J. Nucl. Med. Biol. 1984; 11: 209
    • 10k Barrio JR, Keen RE, Ropchan JR, MacDonald NS, Baumgartner FJ, Padgett HC, Phelps ME. J. Nucl. Med. 1983; 24: 515
    • 10l Zalutsky MR, Wu J, Harper PV, Wickland T. Int. J. Appl. Radiat. Isot. 1981; 32: 182
    • 10m Hübner KF, Andrews GA, Buonocore E, Hayes RL, Washburn LC, Collmann IR, Gibbs WD. J. Nucl. Med. 1979; 20: 507
    • 10n Hayes RL, Washburn LC, Wieland BW, Sun TT, Anon JB, Butler TA, Callahan AP. Int. J. Appl. Radiat. Isot. 1978; 29: 186
  • 11 Shao X, Rodnick ME, Brooks AF, Scott PJ. H In Radiochemical Syntheses, Further Radiopharmaceuticals for Positron Emission Tomography and New Strategies for Their Production. Vol. 2. Scott PJ. H. John Wiley and Sons; Hoboken: 2015: 233
  • 12 Radiochemical conversion was determined by HPLC; %RCC = (area of product radioactivity peak / total area of all radioactive peaks) × 100.
  • 13 Automated Synthesis of [11C-Carbonyl]sarcosine 2 Methylamine hydrochloride (0.5 mg in 50 μL H2O) and 37% formaldehyde (0.56 μL in 50 μL H2O) were added to the reaction vessel of a TRACERLab FXm synthesis module. [11C]NaCN (ca. 900 mCi) was delivered to the reaction vessel from the PETTrace cyclotron, and the reaction was stirred for 5 min at r.t. 10 M NaOH (250 μL) was then added to the reaction vessel and was heated to 60 °C for 5 min to perform the hydrolysis. The crude reaction mixture was cooled, diluted with HPLC mobile phase (0.6 mL), and purified by semipreparative HPLC (column: Phenomenex Luna NH2 250 × 10 mm; mobile phase: 10 mM NaH2PO4 in 60% MeCN, pH 5.6; flow rate: 4 mL/min; t R = 10 min). The fraction corresponding to [11C-carbonyl]sarcosine was collected into 60 mL of Milli-Q water containing 1 M NaOH (0.2 mL), and the resulting solution was passed through a SAX cartridge to trap the radiotracer. The cartridge was washed with sterile water for injection, USP (SWI) and then [11C-carbonyl]sarcosine and eluted with 2 M NaCl (0.5 mL) into a product collection vial precharged with sterile water (4.3 mL) and sodium phosphates, USP (0.2 mL). The SAX cartridge was rinsed with additional SWI (5 mL) to give a final dose of 10 mL. This dose was passed through a 0.22 μm sterile filter into a sterile dose vial and submitted for QC testing (see Supporting Information for details of QC methods). The yield of [11C-carbonyl]sarcosine 2 was 30±12 mCi (n = 3), corresponding to 1% isolated and formulated end-of-synthesis radiochemical yield (RCY) based on [11C]CO2, or 3% based on [11C]HCN). The product was also obtained in high radiochemical purity (RCP ≥90%) and specific activity (SA ≥1500 Ci/mmol using the 0.3 μg/mL HPLC limit-of-detection for sarcosine).
  • 14 General Procedure (Table 3, Entries 1–4) The carbonyl compound (1 equiv) and amine (1–3 equiv) in water and/or EtOH were added to the reaction vessel of a TRACERLab FXm synthesis module. [11C]NaCN (ca. 100–800 mCi) in H2O (200–250 μL) was added, and reaction was stirred for 5–7 min at r.t. to 100 °C. After this time, 10 M NaOH (250–350 μL) was added, and the reaction mixture was heated at 60–100 °C for 5–7 min. The reaction was cooled, diluted, and purified by semipreparative HPLC to yield [11C-carbonyl] methionine 4 (RCY = 5%; RCP >90%; SA = 1256 Ci/mmol), [11C-carbonyl]glycine 5 (RCY = 14%; RCP >95%; SA > 1500 Ci/mmol), or [11C-carbonyl]-N-phenylglycine 6 (RCY = 2%; RCP >99%; SA = 15453 Ci/mmol).
  • 15 Baeza A, Nájera C, Sansano JM. Synthesis 2007; 1230