PET Imaging of Serotonin Transporters with 4-[¹⁸F]-ADAM in a Parkinsonian Rat Model

Abstract

This study was undertaken to address the effects of fetal mesencephalic tissue transplantation on the serotonin system in a rat model of Parkinson's disease (PD) while also investigating the usefulness of 4-[18 F]-ADAM (a serotonin transporter imaging agent) coupled with micro-PET for imaging serotonin transporters (SERTs). A PD model was induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle of the nigrostriatal pathway, while cell transplantation was performed via intrastriatal injection of mesencephalic brain tissue dissected from embryonic (E14) rats. The 4-[18 F]-ADAM/micro-PET scanning was performed following both 6-OHDA lesioning and transplantation. Immunohistochemistry (IHC) studies were also performed following the final PET scan, and the results were compared to show a 17-43% decrease in the specific uptake ratio (SUR) and a 23-52% decrease in serotonin transporter immunoreactivity (SERT-ir) within various brain regions on the lesioned side. The number of methamphetamine-induced rotations also decreased significantly at the 4th week postgraft. In addition, striatal SUR and the SERT-ir levels were restored to 77% and 83% 5 weeks postgraft. These results suggest that Parkinson's disease also affects the serotonergic system, while both the dopaminergic and serotonergic systems can be partially restored in a rat model of PD after E14 mesencephalic tissue transplantation. In addition, we have also determined that 4-[ 18 F]-ADAM/micro-PET can be used to detect serotonergic neuron loss, monitor the progress of Parkinson's disease, and oversee the effectiveness of therapy.

High correlation between in vivo [123I]β-CIT SPECT/CT imaging and post-mortem immunohistochemical findings in the evaluation of lesions induced by 6-OHDA in rats

“…In the rat striatum, DAT concentration is several folds higher than the concentration of SERT, and in normal healthy rat, striatal tissue binding of [ 123 I]β-CIT can be considered to be mediated mainly by DAT [30]. Even though SERT binding activity is decreased in the rat 6-OHDA model [32], there may still be a change in the proportion of striatal DAT versus SERT binding of [ 123 I]β-CIT. In a recent PET study, Sossi et al [33] observed changes in the non-specific background signal from [ 11 C]-methylphenidate (DAT tracer) in the striatum of unilaterally 6-OHDA-lesioned rats.…”

KA-bridged transplantation of mesencephalic tissue and olfactory ensheathing cells in a Parkinsonian rat model

“…Of 24 Parkinsonian rats (PD group) initially scanned by PET, six received a graft consisting of ventral mesencephalic tissue (2 µl) and HBSS (2 µl; VM group), six received a graft consisting of mesencephalic tissue (2 µl) and OECs (2 µl; 2 × 10 5 cells; VM–OECs group), and six received a graft consisting of OECs (2 µl; 2 × 10 5 cells; OECs group). The mesencephalic tissue was dissected from embryonic day 14 (E14) fetal brains (Takeuchi et al ., ), with the dissection area selected according to the protocols of Dunnet and Björklund (Dunnett and Björklund, ) with minor modifications (Weng et al ., ). The dissected tissue blocks contained the ventral mesencephalon and part of the ventral pontine raphe, which contain dopaminergic and serotonergic cell bodies, respectively.…”

“…Considering the partial volume effect between brain regions on voxel‐based PET images (Lehnert et al ., ), the VOIs were bordering within the brain structures. The SUR was expressed as (striatum ‐ cerebellum) / cerebellum, the cerebellum was defined as reference region (Ma et al ., ; Li et al ., ; Weng et al ., ).…”

“…The tissue blocks were maintained in Hank's Buffered Salt Solution (HBSS, Thermo Scientific) during the transplantation procedure. The ventral mesencephalic tissue (Zhou et al ., ; Weng et al ., ) was cut into small pieces and transplanted to restore the nigrostriatal projections to the ipsilateral side of the brain. A glass micropipette was used to inject (in the following order) mesencephalic tissue (4 µl; about 0.5×10 5 cells), air (1 µl), and KA (4 µl; 0.25 µg/µl) to form a bridging track from the substantia nigra to the striatum (0.98 mm anterior to the bregma, 0.25 mm lateral to the midline, 11.5 mm below the dura; at an angle of 60° from vertical) (Zhou et al ., ).…”

“…4‐[ 18 F]–ADAM (14.8 – 18.5 MBq; 0.4 – 0.5 mCi) was injected into the tail veins of normal, PD, and grafted PD (but not including OECs grafted) rats for PET imaging. Micro‐PET image acquisition was performed as previously reported (Ma et al ., ; Li et al ., ; Weng et al ., ) with minor modifications. Briefly, rats were anesthetized by passive inhalation of a mixture of isoflurane/oxygen (5% isoflurane for induction and 2% for maintenance).…”