N-substituted phenyltropanes as in vivo binding ligands for rapid imaging studies of the dopamine transporter

Abstract

Variously substituted phenyltropanes are proven as superb binding ligands for the dopamine transporter (DAT). In this study, we examine four N-substituted phenyltropanes which are derivatives of RTI-55 as in vivo binding ligands in mice. In this series, the methyl group on the nitrogen was replaced by a propyl (RTI-310), an allyl (RTI-311), a butyl (RTI-312), or a fluoropropyl (RTI-313) group. The in vitro binding potencies of these compounds at rat striatal DAT varied somewhat but were about 1 nM. While these compounds did not display marked selectivity for the dopamine transporter, they were more selective than RTI-55. Injection of the radiolabeled compound into mice resulted in striatal-to-cerebellar ratios that varied from about 4.5-6.5. The ratios peaked most rapidly for RTI-311 and RTI-313, at about 20 min. Pharmacological inhibition studies indicated that these compounds were binding to DATs in the striatum, as expected. These findings suggest that some compounds of this type may be excellent in vivo binding ligands for rapid imaging studies of the DAT.

D2 receptor genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans

“…Each subject was injected intravenously with an average of 150 MBq (range 111-186 MBq) of commercially available [ 123 I] FP CIT (GE Healthcare, Amersham, UK) (Booij et al, 1999) that binds to dopamine transporters (Scheffel et al, 1997). Potassium Iodide solution (Lugol) was administered at least 3 h before and 12 h after radiopharmaceutical injection to block thyroid uptake of free radioactive iodide.…”

“…Resting state [ 123 I] FP-CIT measures are directly proportional to affinity or density of DATs and are inversely related to dopamine levels (Scheffel et al, 1997). Striatal D2S autoreceptors regulate DA release and synthesis (Jackson and Westlind-Danielsson, 1994;Lindgren et al, 2003), and they stimulate DAT activity and density (Parish et al, 2001).…”

“…Recent studies suggest an association between relative expression of these two isoforms with an intronic single nucleotide polymorphism of the D2 receptor gene (DRD2 rs1076560 G N T): the minor (T) allele is associated with: reduced relative expression of D2S in striatum and prefrontal cortex (Zhang et al, 2007); inefficient neural cortical and subcortical responses during cognitive processing Zhang et al, 2007); greater emotion control along with more resilient brain activity and reduced in vivo striatal binding of [ 123 I] FP-CIT , a SPECT radioligand which binds to pre-synaptic dopamine transporters (DAT) competing also with local dopamine levels. This last association is consistent with the known role of pre-synaptic D2 receptors in physically and functionally stimulating DATs Lee et al, 2007;Meiergerd et al, 1993;Scheffel et al, 1997).…”

“…Given the above cited evidence of the relationship between D2 receptors and activity of the motor cortex (Hosp et al, 2009;Molina-Luna et al, 2009) and to provide a behavioral correlate of genotype-based differences in brain activity, we also hypothesized a correlation between activity in the cortical motor areas distinguished by genotype and behavioral performance. Moreover, given the known functional and physical interaction between pre-synaptic D2 receptors and DATs Lee et al, 2007;Meiergerd et al, 1993;Scheffel et al, 1997), we explored in vivo the relationship between pre-synaptic striatal dopamine signaling and activity of the motor circuitry, using [ 123 I] FP-CIT SPECT measures of DAT binding and BOLD fMRI (Bertolino et al, 2006.…”

Association of COMT and SLC6A3 polymorphisms with impulsivity, response inhibition and brain function

“…Previous evidence from meta-analyses implies lower striatal DAT expression in 10R homozygotes (Costa et al, 2011;Faraone et al, 2014). Given the primary role of the DAT in transporting extracellular dopamine back into the presynaptic neuron, a genotype with fewer DAT may thus be associated with increased extracellular and reduced intracellular DA (Scheffel et al, 1997). This interpretation is supported by studies of knockout (KO) and knockdown (KD) mice, which either lack the DAT (KO) or show drastically reduced expression (KD).…”