Development and evaluation of radioligands for PET and SPECT imaging of the norepinephrine transporter and the serotonin transporter in vivo

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging can provide quantitative measurements of receptors, transporters and enzymes in living subjects. Radioligands suitable for PET and SPECT imaging of the norepinephrine transporter (NET) and the serotonin transporter (SERT) will provide important tools for studying the pathophysiology and pharmacotherapy of neuropsychiatric disorders. Towards this end, three classes of candidate NET imaging agents and one candidate SERT imaging agent were synthesized and evaluated through in vitro competition assays. The candidate NET ligands were based on pyrrolo[2,1-a]isoquinoline, benzo[ c]thiophene/benzo[c]furan and 3-phenyl-1-indanamine structures, while the candidate SERT ligand, ZIET, is a tropane derivative. Radiosynthetic methods were developed for compounds with promising pharmacology. Radiolabeled candidates were evaluated in rodents and in non-human primates with pharmacologic interventions to determine the specificity and selectivity of ligand binding in vivo.; One of the two pyrroloisoquinoline compounds displayed high affinity for the human NET (hNET) in vitro but was not selective versus the dopamine transporter (hDAT) or the hSERT. Compounds from the benzo[c]thiophene/benzo[ c]furan series possessed the highest affinities and selectivities for the hNET in vitro, but the lead candidates, [11C]talopram and [11C]talsupram, did not readily cross the blood-brain barrier. The phenylindanamine class of compounds contained ligands that were potent for the hNET but were not selective versus the hDAT. Of the NET ligands, trans-N-[11C]methyl-[3-(3-bromophenyl)-indan-1-yl]amine, showed the most promising imaging properties in vivo and will be the basis for further NET ligand development.; The SERT ligand, 2β-carbomethoxy-3β-(4′-(( Z)-2-iodoethenyl)phenyl)tropane (ZIET), possessed high affinity for the hSERT and good in vitro selectivity versus hDAT and hNET. ZIET was labeled with 123I for evaluation in rats and 11C for evaluation in non-human primates. These studies indicate that radiolabeled ZIET binds to SERT sites in the rodent and primate brain and that this class of compounds can be used to image SERT sites in vivo. However, a component of striatal uptake not readily displaceable by SERT ligands was observed in non-human primates, which may reflect DAT binding as well. Future development of tropane-based SERT ligands will focus on derivatives that do not demonstrate non-SERT uptake in the striatum.