3104
J. L. Musachio et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3101–3104
6. Meyer, J. H.; Wilson, A. A.; Sagrati, S.; Hussey, D.;
Carella, A.; Potter, W. Z.; Ginovart, N.; Spencer, E. P.;
Cheok, A.; Houle, S. Am. J. Psychiatry 2004, 161, 826.
7. Volkow, N. D.; Wang, G. J.; Fowler, J. S.; Learned-
Coughlin, S.; Yang, J.; Logan, J.; Schlyer, D.; Gatley, J.
S.; Wong, C.; Zhu, W.; Pappas, N.; Schueller, M.; Jayne,
M.; Carter, P.; Warner, D.; Ding, Y. S.; Shea, C.; Xu, Y.
Biol. Psychiatry 2005, 57, 640.
DAT. Cocaine, which possesses a 25-fold lower affinity
for DAT than 5 (Ki = 423 nM16), has been labeled with
carbon-11 and shown to image the highly abundant
brain DAT in vivo.21 Hence, in retrospect, it is not too
unexpected that [11C]5 (DAT Ki = 16 nM) also labels
and images DAT in vivo.
In conclusion, PET data given for the two ligands pre-
sented in this paper allowed us to state that the first gen-
eration of 11C-labeled N-methyl piperidines shows an
ability to label DAT. While further investigation will
be needed to demonstrate whether these particular li-
gands possess any advantage over the DAT agents cur-
rently used in tomographic imaging,22 it is clear that
ligands of much higher NET affinity and selectivity will
be required from this structural class in order to identify
in vivo imaging tools for the NET. Further extensions of
the SAR studies on this type of ligands are likely to af-
ford the opportunity to discover new NET inhibitors
with higher potency and selectivity that are suitable
for the PET imaging. Related work is underway and will
be reported in due course.
8. Wilson, A. A.; Johnson, D. P.; Mozley, D.; Hussey, D.;
Ginovart, N.; Nobrega, J.; Garcia, A.; Meyer, J.; Houle,
S. Nucl. Med. Biol. 2003, 30, 85.
´ ´ ´
´
9. Schou, M.; Halldin, C.; Sovago, J.; Pike, V. W.; Gulyas,
B.; Mozley, P. D.; Johnson, D. P.; Hall, H.; Innis, R. B.;
Farde, L. Nucl. Med. Biol. 2003, 30, 707.
´ ´ ´
10. Schou, M.; Halldin, C.; Sovago, J.; Pike, V. W.; Hall, H.;
Gulyas, B.; Mozley, P. D.; Dobson, D.; Shchukin, E.;
Innis, R. B.; Farde, L. Synapse 2004, 53, 57.
11. Lin, K. S.; Ding, Y. S.; Kim, S. W.; Kil, K. E. Nucl. Med.
Biol. 2005, 32, 415.
12. Ding, Y. S.; Lin, K. S.; Garza, V.; Carter, P.; Alexoff, D.;
Logan, J.; Shea, C.; Xu, Y.; King, P. Synapse 2003, 50,
345.
13. Andree,B.;Seneca,N.;Schou, M.;Mozley,P.D.;Potter, W.
Z. Eur. J. Nucl. Med. Mol. Imaging 2004, 31(Suppl. 2), S208.
14. Ding, Y.-S.; Lin, K.-S.; Logan, J.; Fowler, J. S.; Volkow,
N. D. J. Nucl. Med. 2004, 45S, 69.
15. Kozikowski, A. P.; Araldi, G. L.; Boja, J.; Meil, W. M.;
Johnson, K. M.; Flippen-Anderson, J. L.; George, C.;
Saiah, E. J. Med. Chem. 1998, 41, 1962.
16. Zhou, J.; He, R.; Johnson, K. M.; Ye, Y.; Kozikowski, A.
P. J. Med. Chem. 2004, 47, 5821.
17. Torres, G. E.; Gainetdinov, R. R.; Caron, M. G. Nat. Rev.
Neurosci. 2003, 4, 13.
18. Wilson, A. A.; Garcia, A.; Jin, L.; Houle, S. Nucl. Med.
Biol. 2000, 27, 529.
Acknowledgments
We are indebted to the National Institute on Drug
Abuse (Grant DA10458) and the NIH/NIMH (Grants
1R41MH070083 and 1R41MH074193) for their support
of these studies. This study was also supported by the
Intramural Research Program of the National Institutes
of Health and National Institute of Mental Health.
19. Logan, J.; Ding, Y. S.; Lin, K. S.; Pareto, D.; Fowler, J.
Nucl. Med. Biol. 2005, 32, 531.
20. The slight increase in striatal uptake for both [11C]5 and
[11C]6 upon pretreatment with desipramine cannot be
explained fully with the currently available data and
further investigation will be needed. For more relevant
information, see references 10 and 12.
21. Fowler, J. S.; Volkow, N. D.; Wolf, A. P.; Dewey, S. L.;
Schlyer, D. J.; Macgregor, R. R.; Hitzemann, R.; Logan,
J.; Bendriem, B.; Gatley, S. J. Synapse 1989, 4, 371.
22. Guilloteau, D.; Chalon, S. Curr. Pharm. Design 2005, 11,
3237.
References and notes
1. Greengard, P. Biosci. Rep. 2001, 21, 247.
2. Malison, R. T. Biol. Psychiatry 1998, 44, 1090.
3. Kim, H. J. J. Nucl. Med. 1997, 38, 1703.
4. Dougherty, D. D. Lancet 1999, 354, 2132; Zhou, J. Drugs
Future 2004, 29, 1235, and references cited therein.
5. Learned-Coughlin, S. M.; Bergstro¨m, M.; Savitcheva, I.;
Ascher, J.; Schmith, V. D.; Langstrom, B. Biol. Psychiatry
2003, 54, 800.