We have finished the development and 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 striatum, respectively. Currently, 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). The precursors of these newly developed brain imaging ligands, L-alpha-MmT and nor-CFT, were synthesized and provided by the chemists in collaborating groups. The in vivo pharmacological data revealed that CFT is a selective inhibitor of dopamine transporters and also a potent indirect dopamine release agent. Iodo-alpha-MmT inhibited tyrosine hydroxylase in the central nervous system. Tomographic imaging of brain dopamine synthesis and/or transporter sites still remains to be investigated. Additionally, we have discovered a neurotransmission role of neuronal L-type calcium channels on the dopaminergic terminals in the brain following its activation by picomoles of MPP(+) with K(+). This MPP(+)-enhanced dopamine release elicited by potassium depolarization was blocked by nimodipine but not by omega-conotoxin GVIA. Furthermore, nimodipine antagonism of Mpp+-potentiated dopamine release increased with depolarization and was highly voltage-dependent. Calcium overload due to a malfunctioning of L-type calcium channels on dopaminergic nerve terminals could trigger a cascade ranged from transmitter overflow to calcium overload and neuronal degeneration. These results could provide an insight on a potential clinical use of calcium antagonists for affective disorders (mania), Alzheimer's disease and Parkinson's disease (dementia), in addition to its current use for a treatment of ischemia during stroke.
