A Second-Generation ^99mTechnetium Single Photon Emission Computed Tomography Agent That Provides in Vivo Images of the Dopamine Transporter in Primate Brain

The dopamine transporter (DAT), located presynaptically on dopamine neurons, provides a marker for Parkinson's disease (Pd) and attention deficit hyperactivity disorder (ADHD). In ADHD, DAT density levels are elevated, while in Pd these levels are depleted. The depletion of DAT levels also corresponds with the loss of dopamine. We now describe the design, synthesis, biology, and SPECT imaging in nonhuman primates of second-generation ^99mtechnetium-based tropane ligands that bind potently and selectively to the DAT. We demonstrate that improved selectivity and biological stability allows sufficient agent to enter the brain and label the DAT in vivo to provide a quantitative measure of DAT density in nonhuman primates. We introduce FLUORATEC (N-[(2-((3‘-N‘-propyl-(1‘ ‘R)-3‘ ‘α-(4-fluorophenyl)tropane-2‘ ‘β-1-propanoyl)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]technetium(V) oxide), a DAT imaging agent that has emerged from these studies and is now in phase 1 clinical trials in the U.S.