F. Zeng et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3044–3047
3047
10
9
8
7
6
5
4
3
2
1
0
References and notes
1. Blakely, R. D.; DeFelice, L. J.; Hartzell, H. C. J. Exp.
Biol. 1994, 196, 263.
2. Galli, A.; DeFelice, L. J.; Duke, B. J.; Moore, K. R.;
Blakely, R. D. J. Exp. Biol. 1995, 198, 2197.
3. Tejani-Butt, S. M.; Yang, J.; Zaffar, H. Brain Res. 1993,
631, 147.
4. Eshleman, A. J.; Carmolli, M.; Cumbay, M.; Martens, C.
R.; Neve, K. A.; Janowsky, A. J. Pharmacol. Exp. Ther.
1999, 289, 877.
5. Klimek, V.; Stockmeier, C.; Overholser, J.; Meltzer, H. Y.;
Kalka, S.; Dilley, G.; Ordway, G. A. J. Neurosci. 1997, 17,
8451.
Caud
Put
Thal
Midbrain
Medulla
Cerebellum
0
20
40
60
80
100
120
140
6. Macey, D. J.; Smith, H. R.; Nader, M. A.; Porrino, L. J. J.
Neurosci. 2003, 23, 12.
Time (min)
7. Van Dort, M. E.; Kim, J. H.; Tluczek, L.; Wieland, D. M.
Nucl. Med. Biol. 1997, 24, 707.
8. Haka, M. S.; Kilbourn, M. R. Nucl. Med. Biol. 1989, 16,
771.
Figure 2. MicroPET baseline study TACs for the brain regions of a
rhesus monkey after intravenous injection of 6.2 mCi of [11C]1.
9. McConathy, J.; Owen, M. J.; Kilts, C. D.; Malveaux, E.
J.; Camp, V. M.; Votaw, J. R.; Nemeroff, C. B.;
Goodman, M. M. Nucl. Med. Biol. 2004, 31, 705.
10. Ding, Y.-S.; Lin, K. S.; Gaza, V.; Carter, P.; Alexoff, D.;
Logan, J.; Shea, C.; Xu, Y.; King, P. Synapse 2003, 50,
345.
11. Wilson, A. A.; Johnson, D. P.; Mozley, D.; Hussey, D.;
Ginovart, N.; Nobrega, J.; Garcia, A.; Meyer, J.; Houls, S.
Nucl. Med. Biol. 2003, 30, 85.
12. 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.
13. 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.
14. Schou, M.; Halldin, C.; Pike, V. W.; Mozley, P. D.;
Dobson, D.; Innis, R. B.; Farde, L.; Hall, H. Eur.
Neuropsychopharmacol. 2005, 15, 517.
15. Seneca, N.; Andree, B.; Sjoholm, N.; Schou, M.; Pauli, S.;
Mozley, P. D.; Stubbs, J. B.; Liow, J. S.; Sovago, J.;
Gulyas, B.; Innis, R.; Halldin, C. Nucl. Med. Commun.
2005, 26, 695.
16. Carroll, F. I. J. Med. Chem. 2003, 46, 1775.
17. Blough, B. E.; Holmquist, C. R.; Abraham, P.; Kuhar, M.
J.; Carroll, F. I. Bioorg. Med. Chem. Lett. 2000, 10, 2445.
18. Carroll, F. I.; Tyagi, S.; Blough, B. E.; Kuhar, M. J.;
Navarro, H. A. J. Med. Chem. 2005, 48, 3852.
19. Boja, J. W.; Kuhar, M. J.; Kopajtic, T.; Yang, E.;
Abraham, P.; Lewin, A. H.; Carroll, F. I. J. Med. Chem.
1994, 37, 1220.
20. Blough, B. E.; Abraham, P.; Lewin, A. H.; Kuhar, M.
J.; Boja, J. W.; Carroll, F. I. J. Med. Chem. 1996, 39,
4027.
21. Holmquist, C. R.; Keverline-Frantz, K. I.; Abraham, P.;
Boja, J. W.; Kuhar, M. J.; Carroll, F. I. J. Med. Chem.
1996, 39, 4139.
8
7
Caud
6
Put
Thal
5
4
Cere
3
2
1
0
Front CX
0
20
40
60
80
100
120
140
Time (min)
Figure 3. Time–activity curves for [11C]1 in an anesthetized rhesus
monkey with RTI-113 (0.3 mg/kg) administered at 60 min postinjec-
tion of [11C]1.
[N-methyl-11C]b-CIT acid which did not enter the brain.
Thus, there was no detectable formation of lipophilic
radiolabeled metabolites capable of entering the brain
and contributing to brain radioactivity.
In summary, we have prepared and determined the mono-
amine transporter binding affinity of several 2b,3a-
(substituted phenyl)nortropanes. The binding results
showed that all of the compounds tested in this series
exhibit great potency for the hNET. Despite the lack of
selectivity of this series of compounds for the hNET vs
hDAT, the most promising compound, [11C]1, was pre-
pared in 45% dcy and evaluated in microPET studies in
a rhesus monkey to assess the imaging properties of this
class of compounds. The regional distribution of radioac-
tivity after injection of [11C]1 showed potential binding to
the NET and DAT in vivo, and further chase andblocking
studies verified this binding. Although 1 has a high affinity
for the hNET in vitro with Ki of 1.78 nM, the high uptake
of [11C]1 in caudate and putamen excludes its utility as a
PET imaging agent for the NET.
22. Zheng, Q.-H.; Mulholland, G. K. Nucl. Med. Biol. 1996,
23, 981.
23. Wilson, A. A.; Houle, S. J. Labelled Compd. Radiopharm.
1999, 42, 1277.
24. Plisson, C.; McConathy, J.; Martarello, L.; Malveaux, E.
J.; Camp, V. M.; Williams, L.; Votaw, J. R.; Goodman,
M. M. J. Med. Chem. 2004, 47, 1122.
25. Lundlvist, C.; Halldin, C.; Swahn, C.-G.; Ginovart, N.;
Farde, L. Nucl. Med. Biol. 1999, 26, 343.