M. Schou et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4843–4845
4845
Baseline
Displacement
600
500
400
300
200
100
0
750
500
250
0
Caudate
Caudate
Putamen
Thalamus
Midbrain
Putamen
Thalamus
Midbrain
Cerebellum
Cerebellum
0
25 50 75 100 125 150 175 200
Time (min)
0
25 50 75 100 125 150 175 200
Time (min)
Figure 2. Time–activity curves following injection with [18F]6. SUV represents standard uptake values (%injected dose per gram tissue multiplied with body weight). The
arrow denotes the administration of the displacement compound, GBR12909.
is of benefit to the patient by reducing the time spent in the PET
camera.
with the experiments. DIMI (Projects EC-FP6, LSVB-CT-2005-
512146) is also gratefully acknowledged for financial support.
The time-course for the metabolism of [18F]6 was studied by
radio-HPLC on acetonitrile extracts from venous monkey plasma.14
The recovery from the analytical procedure was greater than 91%.
Two major radiometabolite fractions were observed, probably cor-
responding to oxidation products of the 3b-benzylic position (i.e.,
to the hydroxyl and carboxylic acid derivatives of [18F]6) as previ-
ously shown for the closely structurally related [11C]1.9 Although it
appears that the 3b-benzylic oxidation product is formed to a low-
er extent as compared after injection of [18F]6 to after injection of
References and notes
1. Aquilonius, S. M.; Bergstrom, K.; Eckernas, S. A.; Hartvig, P.; Leenders, K. L.;
Lundquist, H.; Antoni, G.; Gee, A.; Rimland, A.; Uhlin, J., et al Acta. Neurol. Scand.
1987, 76, 283.
2. Fowler, J. S.; Volkow, N. D.; Wang, G. J.; Gatley, S. J.; Logan, J. Nucl. Med. Biol.
2001, 28, 561.
3. Madras, B. K.; Gracz, L. M.; Fahey, M. A.; Elmaleh, D.; Meltzer, P. C.; Liang, A. Y.;
Stopa, E. G.; Babich, J.; Fischman, A. J. Synapse 1998, 29, 116.
4. Muller, L.; Halldin, C.; Farde, L.; Karlsson, P.; Hall, H.; Swahn, C. G.; Neumeyer,
J.; Gao, Y.; Milius, R. Nucl. Med. Biol. 1993, 20, 249.
[
11C]1, the presence of M1 in plasma warrants further detailed
evaluation of the metabolites of [18F]6 by radio-LC and LC–MS/
MS. This, as well as a more detailed description of the time-course
for metabolite formation in monkeys, will be reported elsewhere.
In summary, a new fluoroethyl analogue of PE2I, compound 6,
was prepared and found to be a potent inhibitor of rodent DAT in
vitro. As a candidate radioligand, 6 was radiolabelled with 18F at
high specific radioactivity and in good radiochemical yield. The
binding of [18F]6 to DAT was specific, reversible and showed faster
kinetics in brain than [11C]1. The possible presence of a hydroxy-
methyl-radiometabolite formed by oxidation in the 3b-benzylic
position of [18F]6 warrants a further detailed evaluation by LC–
MS/MS. This will be reported elsewhere.
5. Goodman, M. M.; Kilts, C. D.; Keil, R.; Shi, B.; Martarello, L.; Xing, D.; Votaw, J.;
Ely, T. D.; Lambert, P.; Owens, M. J.; Camp, V. M.; Malveaux, E.; Hoffman, J. M.
Nucl. Med. Biol. 2000, 27, 1.
6. Halldin, C.; Farde, L.; Lundkvist, C.; Ginovart, N.; Nakashima, Y.; Karlsson, P.;
Swahn, C. G. Synapse 1996, 22, 386.
7. Halldin, C.; Erixon-Lindroth, N.; Pauli, S.; Chou, Y. H.; Okubo, Y.; Karlsson, P.;
Lundkvist, C.; Olsson, H.; Guilloteau, D.; Emond, P.; Farde, L. Eur. J. Nucl. Med.
Mol. Imaging 2003, 30, 1220.
8. Zoghbi, S. S.; Shetty, H. U.; Ichise, M.; Fujita, M.; Imaizumi, M.; Liow, J. S.; Shah,
J.; Musachio, J. L.; Pike, V. W.; Innis, R. B. J. Nucl. Med. 2006, 47, 520.
9. Shetty, H. U.; Zoghbi, S. S.; Liow, J. S.; Ichise, M.; Hong, J.; Musachio, J. L.;
Halldin, C.; Seidel, J.; Innis, R. B.; Pike, V. W. Eur. J. Nucl. Med. Mol. Imaging 2007,
34, 667.
10. Emond, P.; Garreau, L.; Chalon, S.; Boazi, M.; Caillet, M.; Bricard, J.; Frangin, Y.;
Mauclaire, L.; Besnard, J. C.; Guilloteau, D. J. Med. Chem. 1997, 40, 1366.
11. Jucaite, A.; Odano, I.; Olsson, H.; Pauli, S.; Halldin, C.; Farde, L. Eur. J. Nucl. Med.
Mol. Imaging 2006, 33, 657.
12. Stepanov, V.; Schou, M.; Jarv, J.; Halldin, C. Appl. Radiat. Isot. 2007, 65, 293.
13. Zhang, M. R.; Tsuchiyama, A.; Haradahira, T.; Yoshida, Y.; Furutsuka, K.; Suzuki,
K. Appl. Radiat. Isot. 2002, 57, 335.
14. Halldin, C.; Swahn, C.-G.; Farde, L.; Sedvall, G. Radioligand Disposition and
Metabolism. In PET for Drug Development and Evaluation; Comar, D., Ed.; Kluwer
Academic, 1995; pp 55–65.
Acknowledgements
The authors thank Arsalan Amir, Kenneth Dahl, Siv Eriksson, Ju-
lio Gabriel, Guennadi Jogolev, Gudrun Nylén, Phong Truong and the
Karolinska Institutet PET group for excellent technical assistance