HIGHLY POTENT INDANAMINE SEROTONIN UPTAKE BLOCKERS AS RADIOTRACERS FOR IMAGING SEROTONIN UPTAKE SITES

Two highly potent indanamine serotonin (5-HT) uptake blockers, trans-3 '-(4'-bromophenyl)-1-indanamine (trans-[C-11]DBPI or [C-11]Lu 19-056) and its iodo analog, trans-3'(4'-[I-125]iodophenyl)-1-indanamine (tran s-[I-125]DIPI) were evaluated as radiotracers for imaging 5-HT uptake sites in vivo. Trans-[C-11]DBPI was synthesized by N-methylation of th e normethyl precursor with [C-11]iodomethane. Trans-[I-125]DIPI was sy nthesized by iododestannylation of the tributyltin precursor with [I-1 25]NaI. Radiochemical yields for the [C-11] and [I-125] radiotracers w ere 34 and 40%, with specific activities of 4000 and 1800 mCi/mu mol, respectively. In vitro, the iodo analog, trans-DIPI, showed an IC50 va lue of 0.26 nM in inhibition of [H-3]paroxetine binding to 5-HT uptake sites in rat cortex. The potency was found to be equivalent to that o f paroxetine or McN5652. In vivo, after i.v. injection into mice, both radiotracers showed high uptake in brain (3-4% dose/whole brain at 15 min) and high accumulation into target tissues such as hypothalamus a nd olfactory tubercles (7-8% dose/g at 60 min). The binding was blocke d by pre-injection of 5 mg/kg of paroxetine. While the in vivo distrib ution agreed with previously reported 5-HT uptake site distribution, t he radiotracers showed high uptake in non-target tissues such as cereb ellum, resulting in low target-to-non-target ratios (1.5-1.6 at 60 min ). Since washout from non-target regions was slower than from target r egions, longer-time observation with I-125 up to 6 h did not improve t he ratios. HPLC analyses of mouse brain homogenates and blocking studi es indicated that the high uptake in non-target regions is not the res ult of metabolism or any interaction of the radiotracers with those ti ssues via specific binding sites. In spite of low target-to-non-target ratios, target regions with high density of 5-HT uptake sites, such a s the raphe nuclei, superior colliculi and substantia nigra, were visu alized with trans-[I-125]DIPI by ex vivo autoradiography, since the ra diotracer showed high specific binding (total minus nonspecific bindin g).