AbstractBackground[123I]epidepride is a high-affinity radiotracer used in single-photon emission computed tomography (SPECT) imaging of the D2/3 receptors. It binds with high affinity to striatal and extrastriatal receptors. Nevertheless, its slow kinetics in the striatum impedes quantification in this region. Thus, an approach that would allow a simultaneous quantification of both striatal and extrastriatal D2/3 receptors would be of interest for preclinical and clinical SPECT neuroimaging. We describe a partial saturation protocol that allows us to produce an in vivo Scatchard plot and thus estimate Bavail and appKd separately in both striatal and extrastriatal regions, through a single dynamic SPECT session. To validate this approach, a multi-injection protocol is used for the full kinetic modeling of [123I]epidepride using a two-tissue compartment, 5-parameter model (2T-5k).MethodsEighteen male rats were used. Binding parameters were estimated using the multi-injection protocol. Various simulations were performed to estimate the optimal conditions for the partial saturation protocol, which was applied at the region and voxel level. The results of the partial saturation study were compared to those obtained with the 2T-5k model. To illustrate the interest of the partial saturation approach, we performed a preliminary study of the effect of a chronic, subcutaneous administration of haloperidol (1 mg/kg/day), a D2 receptor antagonist, on the Bavail of [123I]epidepride in the rat striatum.ResultsA series of simulations demonstrated that a mass of 3 ug/kg of unlabeled epidepride allows the formation of an in vivo Scatchard plot. The partial saturation study led to robust estimations of Bavail in all brain regions that highly correlated (r = 0.99) with the corresponding values from the multi-injection study. A chronic haloperidol treatment resulted in a 17.9% increase in the Bavail values in the left Caudate Putamen nucleus (CP) (p = 0.07) and a 13.8% increase in the right CP (p = 0.12).ConclusionA partial saturation method allowed the robust quantification of D2/3 receptors in striatal and extrastriatal D2/3 receptors with a single-scan approach. This approach may be applied in the mapping of the D2/3 receptor in translational biological studies and potentially, in clinical SPECT imaging.

01 Dec 2018·Journal of Neurodevelopmental DisordersQ2 · MEDICINE

Dystonia-deafness syndrome caused by ACTB p.Arg183Trp heterozygosity shows striatal dopaminergic dysfunction and response to pallidal stimulation

Q2 · MEDICINE

ArticleOA

Author: Glover, Joel C ; Connelly, James P ; Stray-Pedersen, Asbjørg ; Konglund, Ane ; Jablonski, Greg Eigner ; Skogseid, Inger Marie ; Røsby, Oddveig ; Nedregaard, Bård ; Kvernmo, Nadja

BACKGROUNDDystonia-deafness syndrome is a well-known clinical entity, with sensorineural deafness typically manifesting earlier than dystonia. ACTB p.Arg183Trp heterozygosity has been reported in six patients to cause combined infant-onset deafness and dystonia manifesting in adolescence or young adulthood. Three of these have received beneficial pallidal stimulation. Brain imaging to assess striatal function has not been reported previously, however. Nor has a comprehensive hypothesis been presented for how the pleiotropic manifestations of this specific beta-actin gene mutation originate developmentally.CASE PRESENTATIONA 19-year-old girl with congenital mild dysmorphic facial features, cochlear implants for infant-onset deafness, and mild cognitive and emotional disability, presented with an adolescent-onset, severe generalized dystonia. Brain MRI and multiple single gene sequencing were inconclusive. Due to life-threatening dystonia, we implanted a neurostimulation device, targeting the postero-ventral internal pallidum bilaterally. The Burke-Fahn-Marsden Dystonia Rating Scale motor/disability scores improved from 87/25 to 21/13 at 2.5 months postoperatively, 26/14 at 3 years, and 30/14 at 4 years. Subsequent whole exome sequencing identified heterozygosity for the ACTB p.Arg183Trp variant. Brain imaging included ¹²³I-ioflupane single photon emission computed tomography (Dopamine Transporter-SPECT), SPECT with ¹²³I-epidepride (binds to dopamine type 2-receptors) and ¹⁸ Fluoro-Deoxy-Glucose (FDG)-PET. Both Epidepride-SPECT and FDG-PET showed reduced tracer uptake in the striatum bilaterally, particularly in the putamen. DaT-SPECT was slightly abnormal.CONCLUSIONSIn this patient with dystonia-deafness syndrome caused by ACTB p.Arg183Trp heterozygosity, unprecedented brain imaging findings strongly indicate striatal neuronal/dopaminergic dysfunction as the underlying cause of the dystonia. Pallidal stimulation provided a substantial improvement of the severe generalized dystonia, which is largely sustained at 4-year follow-up, and we advise this treatment to be considered in such patients. We hypothesize that the pleiotropic manifestations of the dystonia-deafness syndrome caused by this mutation derive from diverse developmental functions of beta-actin in neural crest migration and proliferation (facial dysmorphogenesis), hair cell stereocilia function (infant-onset deafness), and altered synaptic activity patterns associated with pubertal changes in striatal function (adolescent-onset dystonia). The temporal differences in developmental onset are likely due to varying degrees of susceptibility and of compensatory upregulation of other actin variants in the affected structures.

01 Sep 2014·Nuclear Medicine and BiologyQ4 · MEDICINE

Dopamine D2/D3 receptor binding of [123I]epidepride in risperidone-treatment chronic MK-801-induced rat schizophrenia model using nanoSPECT/CT neuroimaging

Q4 · MEDICINE

Article

Author: Chang, K W ; Pai, C W ; Chen, M W ; Cheng, K H ; Huang, Y R ; Kuo, W I

INTRODUCTIONEpidepride is a compound with an affinity in picomolar range for D2/D3 receptors. The aim of this work was designed to investigate the diagnostic possibility of [(123)I]epidepride imaging platform for risperidone-treatment chronic MK-801-induced rat schizophrenia model.METHODSRats received repeated administration of MK-801 (dissolved in saline, i.p., 0.3 mg/kg/day) or saline for 4 weeks. After 1-week administration of MK-801, rats in MK-801+risperidone group received risperidone (0.5 mg/kg/day) intraperitoneally 15 min prior to MK-801 administration for the rest of 3-week treatment. We obtained serial [(123)I]epidepride neuroimages from nanoSPECT/CT and evaluated the alteration of specific binding in striatum and midbrain.RESULTSRisperidone reversed chronic MK-801-induced decrease in social interaction duration. IHC and ELISA analysis showed consistent results that chronic MK-801 treatment significantly decreased striatal and midbrain D2R expression but repeated risperidone administration reversed the effect of MK-801 treatment. In addition, [(123)I]epidepride nanoSPECT/CT neuroimaging revealed that low specific [(123)I]epidepride binding ratios caused by MK-801 in striatum and midbrain were statistically alleviated after 1- and 2-week risperidone administration, respectively.CONCLUSIONSWe established a rat schizophrenia model by chronic MK-801 administration for 4 weeks. [(123)I]Epidepride nanoSPECT neuroimaging can trace the progressive alteration of D2R expression in striatum and midbrain caused by long-lasting MK-801 treatment. Besides diagnosing illness stage of disease, [(123)I]epidepride can be a useful tool to evaluate therapeutic effects of antipsychotic drug in chronic MK-801-induced rat schizophrenia model.

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Contrast agents	IND Application	CN	Jiangsu Institute Of Nuclear Medicine	25 Aug 2005

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