We have accomplished the preclinical testing of 6-[F-18]-DOPA and [I-123]- IBZM for a PET imaging of dopaminergic nerve terminals and a SPECT imaging of D-2 dopamine receptors in the brain, respectively. In collaboration with chemists at NIDDK, Research Biochemicals Incorporated and McMaster University Medical Center, we are designing new imaging ligands for a SPECT imaging of tyrosine hydroxylase (iodo-alpha-MmT) and for a PET imaging of cocaine receptor binding sites and/or dopamine transporters (CFT; WIN35428). Preclinical pharmacological data revealed that CFT is a selective inhibitor of dopamine transporters and also a potent indirect dopamine releasing agent. Currently, we are investigating roles of neuronal L-type voltage-sensitive calcium channels on the activation of dopaminergic neurotransmission in the brain following administration of either picomoles of MPP+ or haloperidol. Nimodipine pretreatment antagonized burst firing-evoked dopamine release due to blockade of mesolimbic dopamine receptors by neuroleptics, such as haloperidol. A sustained calcium influx through L-type calcium channels on dopaminergic nerve terminals could trigger a chain of events extending from transmitter overflow to neuronal degeneration. A site-specific generation of hydroxyl radicals (yOH) due to a sustained overflow and autoxidation of striatal dopamine might cause spontaneous degeneration of nigrostriatal dopaminergic neurons as seen during aging and in Parkinson's disease. These results suggest a possible involvement of calcium influx through L-type voltage- sensitive calcium channels in both regulating dopaminergic neurotransmission and promoting generation of reactive hydroxyl free radicals via autoxidation of brain dopamine in vivo.
