Substituted 3-phenyltropane analogs of cocaine: synthesis, inhibition of binding at cocaine recognition sites, and positron emission tomography imaging

Abstract

It is now accepted that (-)-cocaine binds to specific recognition sites associated with monoamine transporters in the mammalian brain. In this study, several analogs of 3 beta-phenyltropane-2 beta-carboxylic acid methyl ester were prepared and their potency for inhibiting the binding of [3H]-3 beta-(4-fluorophenyl)tropane-2 beta-carboxylic acid methyl ester to primate caudate-putamen was evaluated. The synthesis and binding affinity of 3 beta-(3,4- dichlorophenyl)tropane-2 beta-carboxylic acid methyl ester, one of the most potent cocaine congeners yet reported, is presented. The feasibility of synthesizing high-affinity ligands for cocaine recognition sites and their suitability as PET imaging ligands for cocaine receptors in vivo is demonstrated.

Pharmacological Characterization of (E)-N-(4-Fluorobut-2-enyl)-2β-carbomethoxy-3β-(4′-tolyl)nortropane (LBT-999) as a Highly Promising Fluorinated Ligand for the Dopamine Transporter

“…The IC 50 values of GBR12935 and PE2I versus LBT-999 were 2.4 and 18 nM, respectively, and we did not find competition (IC 50 Ͼ 1 M) between LBT-999 and several serotonin transporter ligands [citalopram, paroxetine, and N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine] as well as norepinephrine transporter ligands (nisoxetine and desipramine). This selectivity is higher than that observed in vitro for other DAT ligands from the chemical tropane family such as FPCIT (Neumeyer et al, 1996), FPCBT (Chaly et al, 2004), CFT (Meltzer et al, 1993), FPCT (Goodman et al, 1997), and FECNT (Goodman et al, 2000). The selectivity of LBT-999 as indicated from the in vitro binding data on rat brain was clearly confirmed in the postmortem human autoradiographic study in which it bound highly to the caudate-putamen and only weakly to the thalamus and neocortical areas, as already observed for PE2I (Hall et al, 1999).…”

“…Its in vitro pharmacological properties on rat striatal membranes are very close to those of PE2I . It binds to a single high-affinity site with a moderate affinity (9 nM) closely related to that of other fluorinated tropane derivatives such as FPCIT (Neumeyer et al, 1996), FPCBT (Chaly et al, 2004), CFT (Meltzer et al, 1993), FPCT (Goodman et al, 1997), FECNT (Goodman et al, 2000), and PE2I and has a very high selectivity for the DAT. The IC 50 values of GBR12935 and PE2I versus LBT-999 were 2.4 and 18 nM, respectively, and we did not find competition (IC 50 Ͼ 1 M) between LBT-999 and several serotonin transporter ligands [citalopram, paroxetine, and N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine] as well as norepinephrine transporter ligands (nisoxetine and desipramine).…”

3-Aza-6,8-dioxabicyclo[3.2.1]octanes as new enantiopure heteroatom-rich tropane-like ligands of human dopamine transporter

“…Although studies of structure-activity relationships (SAR) did not provide a comprehensive picture of the binding interaction to DAT at molecular level yet, studies on cocaine and its tropane analogues (see Fig. 1) 8,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] showed that two…”

Technepine: A high-affinity99mtechnetium probe to label the dopamine transporter in brain by SPECT imaging

“…Nevertheless, effective imaging agents have been developed almost exclusively from the phenyltropane analogue of cocaine WIN 35,428 or CFT, a potent dopamine transport inhibitor (Clarke et al, 1973;Heikkila et al, 1979). The impetus for developing [llC]WIN 35,428 as a PET ligand (Hantraye et al, 1992;Madras, 1994;Madras et al, 1991Madras et al, , 1994Wong et al, 1993;Meltzer et al, 1993) and y-emitting analogues for SPECT imaging (e.g., RTI-55, the 4-iodophenyl analogue of WIN 35,428, Canfield et al, 1990;Boja et al, 1991;Innis et al, 1991) arose directly from our observations of the binding of WIN 35,428 to the dopamine transporter. Unlike previous dopamine transport inhibitors (noncocaine congeners) proposed for brain imaging (Kuhar et a1.,1990), the radiolabeled form of WIN 35,428 binds to the dopamine transporter in brain striatum with very low levels of nonspecific binding (Madras et al, 1989a,b) and distributes principally to dopamine-rich regions of brain, as we reported in 1989 (Canfield et al, 1989) and subsequently (Canfield et al, 1990;Kaufman and Madras, 1992).…”