Synthesis 2019; 51(23): 4374-4384
DOI: 10.1055/s-0039-1690522
special topic
© Georg Thieme Verlag Stuttgart · New York

Preparation of the Serotonin Transporter PET Radiotracer 2-({2-[(Dimethylamino)methyl]phenyl}thio)-5-[18F]fluoroaniline (4-[18F]ADAM): Probing Synthetic and Radiosynthetic Methods

Molecular Imaging Chemistry Laboratory, Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0SZ, UK   Email: sms96@cam.ac.uk
,
Xiaoyun Zhou
,
,
Franklin I. Aigbirhio
› Author Affiliations
This work was in part funded by an internal grant from the Behavioural and Clinical Neuroscience Institute (BCNI), University of Cambridge.
Further Information

Publication History

Received: 26 June 2019

Accepted after revision: 25 July 2019

Publication Date:
21 August 2019 (eFirst)

Published as part of the Special Topic Halogenation methods (with a view towards radioimaging applications)

Abstract

Serotonin transporters (SERTs) are involved in regulating the concentration of synaptic serotonin and present a good target for many neurologic and psychiatric disorder drugs. Positron-emission tomography (PET) is a valuable tool in both diagnosis and monitoring treatment therapies, and hence much effort is being given to developing suitable PET agents for imaging SERT. Our interest in applying the fluorine-18 analogue 4-[18F]ADAM for imaging SERT prompted the development of an improved synthetic route to access unlabelled ADAM. This is achieved using Pd-catalysed coupling with thiosalicylic acid and an EDC/HOBt amide coupling in 36% yield over 4 steps. A novel radiolabelling precursor, the pinacol-derived boronic ester, is prepared from the bromide using the Miyaura borylation and is obtained in 27% yield over 6 steps. Pinacolate is then used for the radiolabelling of 4-[18F]ADAM based on Cu-mediated nucleophilic fluorination in which the presence of oxygen is critical for the reaction. A 1:1 substrate to copper ratio is found to be optimal when the reaction is performed in dimethylacetamide at 85 °C. Using these conditions, 4-[18F]ADAM is prepared in 29 ± 10% (n = 6) radiochemical conversion after hydrolysis of the Boc group with HCl. Furthermore, the method is successfully automated to afford 4-[18F]ADAM in 10% radiochemical conversion.

Supporting Information

 
  • References

  • 1 Ma KH, Huang WS, Kuo YY, Peng CJ, Liou NH, Liu RS, Hwang JJ, Liu JC, Chen HJ, Shiue CY. Neuroimage 2009; 45: 687
  • 2 Sephton SM, Ametamey SM. Positron Emission Tomography Agents . In Molecular Imaging Techniques: New Frontiers . Gazeau F. Future Medicine; London: 2013. DOI 10.4155/ebo.12.504
  • 3 Brust P, Hesse S, Muller U, Szabo Z. Curr. Psychiatry Rev. 2006; 2: 111
  • 4 Kim SE, Choi JY, Choe YS, Choi Y, Lee WY. J. Nucl. Med. 2003; 44: 870
  • 5 Li I.-H, Huang W.-S, Yeh C.-B, Liao M.-H, Chen C.-C, Shen L.-H, Liu J.-C, Ma K.-H. Nucl. Med. Biol. 2009; 36: 605
  • 6 Kerenyi L, Ricaurte GA, Schretlen DJ, McCann U, Varga J, Mathews WB, Ravert HT, Dannals RF, Hilton J, Wong DF, Szabo Z. Arch. Neurol. 2003; 60: 436
  • 7 Guttman M, Boileau I, Warsh J, Saint-Cyr JA, Ginovart N, McCluskey T, Houle S, Wilson A, Mundo E, Rusjan P, Meyer J, Kish SJ. Eur. J. Neurol. 2007; 14: 523
  • 8 Weng S.-J, Shiue C.-Y, Huang W.-S, Cheng C.-Y, Huang S.-Y, Li I, Tao C.-C, Chou T.-K, Liao M.-H, Chang Y.-P, Ma K.-H. Cell Transplant. 2013; 22: 1295
  • 9 Houle S, Ginovart N, Hussey D, Meyer JH, Wilson AA. Eur. J. Nucl. Med. 2000; 27: 1719
  • 10 Wilson AA, Ginovart N, Schmidt M, Meyer JH, Threlkeld PG, Houle S. J. Med. Chem. 2000; 43: 3103
  • 11 Huang W.-S, Huang S.-Y, Ho P.-S, Ma K.-H, Huang Y.-Y, Yeh C.-B, Liu R.-S, Cheng C.-Y, Shiue C.-Y. Eur. J. Nucl. Med. Mol. Imaging 2013; 40: 115
  • 12 Hesse S, Brust P, Mäding P, Becker G.-A, Patt M, Seese A, Sorger D, Zessin J, Meyer PM, Lobsien D, Laudi S, Habermann B, Füchtner F, Luthardt J, Bresch A, Steinbach J, Sabri O. Eur. J. Nucl. Med. Mol. Imaging 2012; 39: 1001
  • 13 Huang YY, Huang WS, Ma KH, Chou TK, Kuo YY, Cheng CY, Shiue CY. Appl. Radiat. Isot. 2012; 70: 2298
  • 14 Chen Y.-A, Huang W.-S, Lin Y.-S, Cheng C.-Y, Liu R.-S, Wang S.-J, Li I.-H, Huang S.-Y, Shiue C.-Y, Chen C.-Y, Ma K.-H. Nucl. Med. Biol. 2012; 39: 279
  • 15 Tredwell M, Preshlock SM, Taylor NJ, Gruber S, Huiban M, Passchier J, Mercier J, Génicot C, Gouverneur V. Angew. Chem. Int. Ed. 2014; 53: 7751
  • 16 Preshlock S, Calderwood S, Verhoog S, Tredwell M, Huiban M, Hienzsch A, Gruber S, Wilson TC, Taylor NJ, Cailly T, Schedler M, Collier TL, Passchier J, Smits R, Mollitor J, Hoepping A, Mueller M, Genicot C, Mercier J, Gouverneur V. Chem. Commun. 2016; 52: 8361
  • 17 Shiue GG, Fang P, Shiue C.-Y. Appl. Radiat. Isot. 2003; 58: 183
  • 18 Peng CJ, Huang YY, Huang WS, Shiue CY. Appl. Radiat. Isot. 2008; 66: 625
  • 19 Huang Y.-Y, Huang W.-S, Chu T.-C, Shiue C.-Y. Appl. Radiat. Isot 2009; 67: 1063
  • 20 Blakemore PR, Kilner C, Milicevic SD. J. Org. Chem. 2005; 70: 373
  • 21 Evans V, Mahon MF, Webster RL. Tetrahedron 2014; 70: 7593
  • 22 Lam PY, Clark CG, Saubern S, Adams J, Winters MP, Chan DM, Combs A. Tetrahedron Lett. 1998; 39: 2941
  • 23 Shiue GG, Fang P, Shiue CY. Appl. Radiat. Isot. 2003; 58: 183