ACS Medicinal Chemistry Letters
Letter
SV2A is the binding site for the antiepileptic drug levetiracetam. Proc.
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approach for PET imaging of SV2A expression and facilitate
further clinical translation studies.
ASSOCIATED CONTENT
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S
* Supporting Information
(10) Mendoza-Torreblanca, J. G.; Vanoye-Carlo, A.; Phillips-Farfan,
B. V.; Carmona-Aparicio, L.; Gomez-Lira, G. Synaptic vesicle protein
2A: basic facts and role in synaptic function. Eur. J. Neurosci. 2013, 38,
3529−39.
Representative experimental procedures and NMR, MS, and
HPLC data for all new test compounds, and micro-PET
imaging. This material is available free of charge via the Internet
(11) Hildenbrand, S.; Baqi, Y.; Muller, C. E. Synthesis of tritium-
̈
labeled levetiracetam ((2S)-2-(2-oxopyrrolidin-1-yl)butanamide) with
high specific activity. J. Labelled Compd. Radiopharm 2011, 55, 48−51.
(12) Wong, D. F.; Tauscher, J.; Grunder, G. The role of imaging in
proof of concept for CNS drug discovery and development.
Neuropsychopharmacology 2009, 34, 187−203.
(13) Bretin, F.; Warnock, G.; Bahri, M. A.; Aerts, J.; Mestdagh, N.;
Buchanan, T.; Valade, A.; Mievis, F.; Giacomelli, F.; Lemaire, C.;
Luxen, A.; Salmon, E.; Seret, A.; Plenevaux, A. Preclinical radiation
dosime-try for the novel SV2A radiotracer [18F]UCB-H. EJNMMI Res.
2013, 3, 35−42.
(14) Mercier, J.; Archen, L.; Bollu, V.; Carre, S.; Evrard, Y.; Jnoff, E.;
Kenda, B.; Lallemand, B.; Michel, P.; Montel, F.; Moureau, F.; Price,
N.; Quesnel, Y.; Sauvage, X.; Valade, A.; Provins, L. Discovery of
heterocyclic nonacetamide synaptic vesicle protein 2A (SV2A) ligands
with single-digit nanomolar potency: opening avenues towards the first
SV2A positron emission tomography (PET) ligands. ChemMedChem
2014, 9, 693−698.
AUTHOR INFORMATION
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Corresponding Author
*(H.C.) Phone: +1-214-645-4992. Fax: +1-214-645-0837. E-
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We would like to thank staff members from the Children’s
Hospital of Michigan PET center for their service and support,
and thank Prof. David Crich from Department of Chemistry in
Wayne State University for the help of setup of Barton
decarboxylation protocol. Dr. Guochao Liao from Wayne State
University and Dr. Yongjun Li from Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences are acknowl-
edged for help of chemical analysis and discussion.
(15) Warnock, G. I.; Aerts, J.; Bahri, M. A.; Bretin, F.; Lemaire, C.;
Giacomelli, F.; Mievis, F.; Mestdagh, N.; Buchanan, T.; Valade, A.;
Mercier, J.; Wood, M.; Gillard, M.; Seret, A.; Luxen, A.; Salmon, E.;
Plenevaux, A. Evaluation of 18F-UCB-H as a novel PET tracer for
synaptic vesicle protein 2A in the brain. J. Nucl. Med. 2014, 55, 1−6.
(16) Josephson, L.; Rudin, M. Barriers to clinical translation with
diagnostic drugs. J. Nucl. Med. 2013, 54, 329−332.
ABBREVIATIONS
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LEV, levetiracetam, (S)-α-ethyl-2-oxo-1-pyrrolidine acetamide;
SV2A, synaptic vesicle protein 2A; 11C-LEV, 11C-levetiracetam;
CNS, central nervous system; AEDs, antiepileptic drugs; PET,
positron emission tomography; LEV-ene, N-allyl-2-pyrrolidone;
THF, tetrahydrofuran; iso-LEV-ene, 1-propenyl-pyrrolidin-2-
one; LDA, lithium diisopropylamide; KHMDS, potassium
bis(trimethylsilyl)amide; LEV acid, (2S)-2-(2-oxopyrrolidin-1-
yl)butanoic acid; EOB, end of bombardment; EOS, end of
synthesis
(17) Rotstein, B. H.; Liang, S. H.; Holland, J. P.; Collier, T. L.;
Hooker, J. M.; Wilson, A. A.; Vasdev, N. 11CO2 fixation: a renaissance
in PET radiochemistry. Chem. Commun. 2013, 49, 5621−5629.
(18) Boschia, F.; Campsa, P.; Comes-Franchinib, M.; Munoz-
̃
Torreroa, D.; Riccib, A.; Sanchez, L. A synthesis of levetiracetam based
on (S)-N-phenylpantolactam as a chiral auxiliary. Tetrahedron:
Asymmetry 2005, 16, 3739−3745.
(19) Neugnot, B.; Cintrat, J.-C.; Rousseau, B. A new highly
chemoselective isomerization of allylamides. Tetrahedron 2004, 60,
3575−3579.
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