Communications to the Editor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4431
(4) Madras, B. K.; J ones, A. G.; Mahmood, A.; Zimmerman, R. E.;
Garada, B.; Holman, B. L.; Davison, A.; Blundell, P.; Meltzer,
P. C. Technepine: a high-affinity 99mTechnetium probe to label
the dopamine transporter in brain by SPECT imaging. Synapse
(N. Y.) 1996, 22, 239-246.
(5) (a) Kung, M. P.; Stevenson, D. A.; Plo¨ssl, K.; Meegalla, S. K.;
Beckwith, A.; Essman, W. D.; Mu, M.; Lucki, I.; Kung, H. F.
[Tc-99m]TRODAT-1: A novel technetium-99m complex as a
dopamine transporter imaging agent. Eur. J . Nucl. Med. 1996,
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minergic drugs on in vivo binding of [99mTc]TRODAT-1 to the
central dopamine transporters in rats. Eur. J . Nucl. Med. 1998,
25, 31-39.
Ta ble 1. Binding Data (IC50 Values) of â-Cft, 3, and 4 to the
Monoamine Transportersa
DAT high
affinity (nM) affinity (nM)
DAT low
NET
(nM)
5-HTT
(nM)
â-CFT 2.62 ( 1.06
139 ( 72
5.69 ( 1.20
20.3 ( 16.1
834 ( 4517 759 ( 4717
3
4
0.227 ( 0.202
0.146 ( 0.042
16.3 ( 0.6
7.3 ( 1.1
28.5 ( 4.6
71.8 ( 1.4
a
Data are means ( SEM (n ) 3-4).
The most important result is the markedly enhanced
affinity of the tricarbonylrhenium(I) complex 4 in
comparison with â-CFT. Although other metal com-
plexes exhibit a very high affinity to the DAT, for
(6) Meegalla, S. K.; Plo¨ssl, K.; Kung, M. P.; Chumpradit, S.;
Stevenson, D. A.; Kushner, S. A.; McElgin, W. T.; Mozley, P. D.;
Kung, H. F. Synthesis and characterization of technetium-99m-
labeled tropanes as dopamine transporter-imaging agents. J .
Med. Chem. 1997, 40, 9-17.
example, a “3 + 1” complex derived from IPT,20
a
cyclopentadienyl carbonyl complex derived from â-CIT,21
and technepine again derived from â-CFT,4 the affinity
was more or less retained in the same order of magni-
tude compared to the starting ligand. With complex 4,
we achieved an affinity of about 1 order of magnitude
higher than that of â-CFT. This can only be explained
by participation of the complex unit in the binding to
the transporter in the sense that the assumed hydrogen
bonding between the C-2 ester group and the DAT is
complemented by an additional lipophilic interaction
exerted by the sulfur atoms of the dithioether. This
lipophilic interaction can slightly be enhanced by com-
plexation. This interpretation is consistent with previ-
ously reported results from Kozikowski et al. regarding
a 2-cocaine analogue bearing a 2-vinyl substituent22 and
of Carroll et al. regarding cocaine analogues with
heterocyclic substituents in position 2.23 Both reports
suggest a weak hydrophobic contribution to binding at
the DAT.
(7) European Patent Application 972012322.
(8) Reisgys, M.; Wu¨st, F.; Alberto, R.; Schibli, R.; Schubiger, P. A.;
Pietzsch, H. J .; Spies, H.; J ohannsen, B. Synthesis of rhenium-
(I) and technetium(I) carbonyl/dithioether ligand complexes
bearing 3,17â-estradiol. Bioorg. Med. Chem. Lett. 1997, 7, 2243-
2246.
(9) Meegalla, S. K.; Plo¨ssl, K.; Kung, M. P.; Stevenson, D. A.; Mu,
M.; Kushner, S. A.; Liable-Sands, L. M.; Rheingold, A. L.; Kung,
H. F. Specifity of diastereomers of [99mTc]TRODAT-1 as dopa-
mine transporter imaging agents. J . Med. Chem. 1998, 41, 428-
436.
(10) Meltzer, P. C.; Blundell, P.; Madras, B. K. Structure activity
relationships of inhibition of the dopamine transporter by
3-arylbicyclo[3.2.1]octanes. Med. Chem. Res. 1998, 8, 12-34.
(11) Lewin, A. H.; Gao, Y.; Abraham, P.; Boja, J . W.; Kuhar, M. J .;
Carroll, F. I. 2â-Substituted analogues of cocaine. Synthesis and
inhibition of binding to the cocaine receptor. J . Med. Chem. 1992,
35, 135-140.
(12) Kozikowski, A. P.; Saiah, M. K. E.; J ohnson, K. M.; Bergmann,
J . S. Chemistry and Biology of the 2â-Alkyl-3â-phenyl Analogues
of Cocaine: Subnanomolar Affinity Ligands that Suggest a New
Pharmacophore Model at the C-2 Position. J . Med. Chem. 1995,
38, 3086-3093.
(13) Carroll, F. I.; Kotian, P.; Gray, J . L.; Abraham, P.; Kuzemko,
M. A.; Lewin, A. H.; Boja, J . W.; Kuhar, M. J . 3â-(4′-chlorophen-
yl)tropan-2â-carboxamides and cocaine amide analogues: new
high affinity and selective compounds for the dopamine trans-
porter. Med. Chem. Res. 1993, 7, 468-472.
(14) Xu, L. F.; Trudell, M. L. Stereoselective synthesis of 2â-
carbomethoxy-3â-phenyltropane derivatives. Enhanced stereo-
selectivity observed for the conjugate addition reaction of
phenylmagnesium bromide derivatives with anhydrous dichlo-
romethane. J . Heterocycl. Chem. 1996, 33, 2037-2039.
(15) Madras, B. K.; Spealman, R. D.; Fahey, M. A.; Neumeyer, J . L.;
Saha, J . K.; Milius, R. A. Cocaine receptors labeled by [3H]2â-
carbomethoxy-3â-(4-fluorophenyl)tropane. Mol. Pharmacol. 1989,
36, 518-524.
(16) Reith, M. E. A.; Xu, C.; Coffey, L. L. Binding domains for blockers
and substrates on the cloned human dopamine transporter
studied by protection against n-ethylmaleimide-induced reduc-
tion of [3H]2â-carbomethoxy-3â-(4-fluorophenyl) tropane ([3H]-
WIN35,428) binding. Biochem. Pharmacol. 1996, 52, 1435-1446.
(17) Boja, J . W.; Kuhar, M. J .; Kopajtic, T.; Yang, E.; Abraham, P.;
Lewin, A. H.; Carroll, F. I. Secondary amine analogues of 3â-
(4′-substituted phenyl)tropane-2â-carboxylic acid esters and
N-norcocaine exhibit enhanced affinity for serotonin and nore-
pinephrine transporters. J . Med. Chem. 1994, 37, 1220-1223.
(18) Gracz, L. M.; Madras, B. K. [3H]WIN 35,428 ([3H]CFT) binds to
multiple charge-states of the solubilized dopamine transporter
in primate striatum. J . Pharmacol. Exp. Ther. 1995, 273, 1224-
1234.
Con clu sion s. TROTEC-1 (4) represents the first
example of a dithioether/carbonyl complex with excep-
tional high affinity to the DAT. We have thus demon-
strated that the Tc-complexed chelator moiety, rather
than necessarily representing an obstacle to binding as
a consequence of its steric bulk, may in favorable cases
even improve binding through additional interactions
if its position within the ligand molecule is chosen
judiciously.
Additional studies focused on the biodistribution
behavior of the 99mTc complex and the question of which
structural features influence the pharmacological activ-
ity of further dithioether/carbonyl complexes are cur-
rently in progress.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
scriptions of the chemistry and radioligand binding assays (4
pages). Ordering information is given on any current mast-
head page.
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