141807-58-1

The synthesis of an N2S2 conjugated BAT phenyltropane ligand is described. This agent can be further used to incorporate technetium-99m to form a neutral complex for SPECT imaging of the dopamine transporter.

A series of dimeric phenyl tropanes consisting of two molecules of 4-chloro, 4-iodo or 4-(3-thiopheno)-phenyl tropane tethered together at the carboxylic acid moiety by a diamine or diol linker were prepared. The diamines used were a variety of linear, cyclic and aromatic diamines, while the diol tethered compounds were prepared by 'click' chemistry and contained a triazole in the linker. The new compounds were tested for binding to hDAT, hSERT and hNET. Amide linked chlorophenyl tropanes with an aromatic linker was found to be potent and selective DAT inhibitors with the best Ki value for hDAT being 6 nM. The ester linked halophenyl tropanes were more potent but displayed little selectivity in inhibition of monoamine transporter binding. Among the studied compounds an ester linker of 10 atoms between the tropane moieties gave the highest affinity. One monomeric phenyl tropane was made for comparison and was found to be less potent than the dimeric counterparts towards SERT and NET but remain highly active against DAT. Dimeric thiophenophenyl tropanes were in general found to be comparatively poor monoamine transporter binders, but significant gains of affinity of up to 45-fold could be achieved with selected dimeric chlorophenyl tropanes compared to the parent monomer. This observation implies that a secondary binding site that has affinity for phenyl tropanes, most likely the putative S2 site, is located within 13 A of the primary central S1 binding site.

A series of novel fluoroalkyl-containing tropane derivatives were synthesized from cocaine. The binding affinities for DAT, SERT, and NET were determined via competitive binding assays. A series of novel fluoroalkyl-containing tropane derivatives (6-8, 10

An iodinated neuroprobe is provided for mapping monoamine reuptake sites. The iodinated neuroprobe is of the formula: wherein R=a CnH2n+1 group where n=0-6, an alkenyl group, a monofluoroalkyl group including nF where n=18 or 19, or a mCnH2n+1 gro

A series of novel fluoroalkyl-containing tropane derivatives was synthesized, and their binding affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) were determined via competitive binding assays. Among these derivatives, the fluoropropyl ester of β-CIT (19), the fluoroethyl ester of β-CIT (20), the N-fluoropropyl derivative of β-CBT (12), and the fluoropropyl ester of β-CMT (18) displayed higher affinity and greater selectivity for the DAT versus SERT and NET than FP-CIT, which indicates that they are attractive candidates for the development of 18F-labeled PET imaging agents for the DAT.

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An iodinated neuroprobe is provided for mapping monoamine reuptake sites. The iodinated neuroprobe is of the formula: STR1 wherein: R=aryl, substituted aryl, heterocyclic, CO(CH2)n Y, (CH2)n CHF2, and

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Several 2β-carboxylic acid ester and amide analogues of cocaine and of 3β-(4'-substituted phenyl)tropane-2β-carboxylic acid were prepared. The binding affinities of these compounds, and of some previously prepared analogues, at the dopamine (DA), norepinephrine (NE), and serotonin (5-HT) transporters were determined. The phenyl esters of 3β-(4'-methylphenyl)and 3β-(4'-chlorophenyl)tropane-2β-carboxylic acid are highly potent and highly selective for the DA transporter. The isopropyl esters of 3β-(4'- chlorophenyl)- and 3β-(4'-iodophenyl)tropane-2β-carboxylic acid also possess high DA affinity and show significant DA transporter selectivity. Similarly, the phenyl and isopropyl ester analogues of cocaine are much more selective for the DA transporter than cocaine. Tertiary amide analogues of cocaine and of 3β-(4'-substituted phenyl)tropane-2β-carboxylic acids are more potent inhibitors of radioligand binding at the DA transporter than the primary and secondary amide analogues. In particular, 3β-(4'- chlorophenyl)tropane-2β-N-morpholinocarboxamide as well as the 3β-(4'- chlorophenyl)- and 3β-(4'-iodophenyl)tropane-2β-N-pyrrolidinocarboxamides possess high affinity and selectivity for the DA transporter. The N,N- dimethylamide cocaine analogue is the most selective cocaine amide derivative for the DA transporter. High correlation between the inhibition of radioligand binding and inhibition of uptake at the DA, NE, and 5-HT transporter was found for a selected group of analogues. Within this group, one compound, the isopropyl ester of 3β-(4'-iodophenyl)-tropane-2β- carboxylic acid, was found to be more potent in the inhibition of radioligand binding than in the inhibition of DA uptake. Taken together with its high potency and selectivity at the DA transporter, this suggests that this compound may be a lead in the development of a cocaine antagonist.

An iodinated neuroprobe is provided for mapping monoamine reuptake sites. The iodinated neuroprobe is of the formula: STR1 wherein R=a Cn H2n+1 group where n=0-6, an alkenyl group, a monofluoroalkyl group including n F whe

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