Reference Region Modeling Approaches for Amphetamine Challenge Studies with [<sup>11</sup>C]FLB 457 and PET

Sandiego, Christine; Gallezot, Jean‐Dominique; Lim, Keunpoong; Ropchan, Jim; Lin, Shu-fei; Gao, Hong; Morris, Evan D.; Cosgrove, Kelly P.

doi:10.1038/jcbfm.2014.237

Cited by 71 publications

(74 citation statements)

References 30 publications

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“…Since the current BP ND values in target regions are relatively high (>15), a relatively large maximum difference in BP ND estimates by SRTM can be anticipated. Similar observations have previously been reported for several other radioligands, including [ 11 C]Cimbi-36, [ 11 C]WAY-100635 and [ 11 C]FLB 457 [24, 33–35]. As for these established radioligands, reference tissue models may be considered for quantification of [ 11 C]Lu AE92686 binding in NHP studies in particular when multiple PET measurements are performed on the same subject such as in pharmacological challenge studies [32, 34, 36].…”

Section: Discussionsupporting

confidence: 88%

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

Yang

Степанов

Amini

et al. 2016

Eur J Nucl Med Mol Imaging

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Purpose[11C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [11C]Lu AE92686 has high affinity for PDE10A (IC 50 = 0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [11C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain.MethodsA total of 11 PET measurements, seven baseline and four following pretreatment with unlabeled Lu AE92686 or the structurally unrelated PDE10A inhibitor MP-10, were performed in five NHPs using a high resolution research tomograph (HRRT). [11C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches.ResultsRegional time-activity curves were best described with the two-tissue compartment model (2TCM). However, the distribution volume (V T) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar V T values could not be derived by the 2TCM. For cerebellum, a proposed reference region, V T values increased by ∼30 % with increasing PET measurement duration from 63 to 123 min, while V T values in target regions remained stable. Both pretreatment drugs significantly decreased [11C]Lu AE92686 binding in target regions, while no significant effect on cerebellum was observed. Binding potential (BP ND) values, derived with the simplified reference tissue model (SRTM), were 13–17 in putamen and 3–5 in substantia nigra and correlated well to values from the Logan plot analysis.ConclusionsThe method proposed for quantification of [11C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [11C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-016-3544-9) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 88%

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

Yang

Степанов

Amini

et al. 2016

Eur J Nucl Med Mol Imaging

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“…The VCTR was administered the day prior to amphetamine administration (pre-amphetamine condition) and again 100 minutes following amphetamine administration (post-amphetamine condition). This time point was chosen to fall within or near the peak plasma amphetamine level [87]. Figure 1C illustrates the timing of PET scans and VCTR task sessions.…”

Section: Star Methodsmentioning

confidence: 99%

A Perceptual Inference Mechanism for Hallucinations Linked to Striatal Dopamine

et al. 2018

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Hallucinations, a cardinal feature of psychotic disorders such as schizophrenia, are known to depend on excessive striatal dopamine. However, an underlying cognitive mechanism linking dopamine dysregulation and the experience of hallucinatory percepts remains elusive. Bayesian models explain perception as an optimal combination of prior expectations and new sensory evidence, where perceptual distortions such as illusions and hallucinations may occur if prior expectations are afforded excessive weight. Such excessive weight of prior expectations, in turn, could stem from a gain-control process controlled by neuromodulators such as dopamine. To test for such a dopamine-dependent gain-control mechanism of hallucinations, we studied unmedicated patients with schizophrenia with varying degrees of hallucination severity and healthy individuals using molecular imaging with a pharmacological manipulation of dopamine, structural imaging, and a novel task designed to measure illusory changes in the perceived duration of auditory stimuli under different levels of uncertainty. Hallucinations correlated with a perceptual bias, reflecting disproportional gain on expectations under uncertainty. This bias could be pharmacologically induced by amphetamine, strongly correlated with striatal dopamine release, and related to cortical volume of the dorsal anterior cingulate, a brain region involved in tracking environmental uncertainty. These findings outline a novel dopamine-dependent mechanism for perceptual modulation in physiological conditions and further suggest that this mechanism may confer vulnerability to hallucinations in hyper-dopaminergic states underlying psychosis.

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“…Although few studies suggest small specific binding of [ 11 C]FLB457 in cerebellum, no change in cerebellar distribution volume was observed following challenges with amphetamine and methylphenidate . Previous studies with [ 11 C]FLB457 have successfully used SRTM with cerebellum as a reference region (eg, Ko et al, Mizrahi et al), and a recent study showed that SRTM is a valid modelling approach to measure the percentage change in BP ND (

{∆ italicBP}_{ND} = 1 - {BP}_{ND}^{Stress} / {BP}_{ND}^{Control}

) with [ 11 C]FLB457 . Right and left ROIs were pooled together to create a single TAC used to derive the BP ND .…”

Section: Methodsmentioning

confidence: 99%

Stress‐induced cortical dopamine response is altered in subjects at clinical high risk for psychosis using cannabis

et al. 2019

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Stress and cannabis use are risk factors for the development of psychosis. We have previously shown that subjects at clinical high risk for psychosis (CHR) exhibit a higher striatal dopamine response to stress compared with healthy volunteers (HV), with chronic cannabis use blunting this response. However, it is unknown if this abnormal dopamine response extends to the prefrontal cortex (PFC). Here, we investigated dorsolateral PFC (dlPFC) and medial PFC (mPFC) dopamine release using [11C]FLB457 positron emission tomography (PET) and a validated stress task. Thirty‐three participants completed two PET scans (14 CHR without cannabis use, eight CHR regular cannabis users [CHR‐CUs] and 11 HV) while performing a Sensory Motor Control Task (control scan) and the Montreal Imaging Stress Task (stress scan). Stress‐induced dopamine release (ΔBPND) was defined as percent change in D2/3 receptor binding potential between both scans using a novel correction for injected mass of [11C]FLB457. ΔBPND was significantly different between groups in mPFC (F(2,30) = 5.40, .010), with CHR‐CUs exhibiting lower ΔBPND compared with CHR (.008). Similarly, salivary cortisol response (ΔAUCI) was significantly lower in CHR‐CU compared with CHR (F(2,29) = 5.08, .013; post hoc .018) and positively associated with ΔBPND. Furthermore, CHR‐CUs had higher attenuated psychotic symptoms than CHR following the stress task, which were negatively associated with ΔBPND. Length of cannabis use was negatively associated with ΔBPND in mPFC when controlling for current cannabis use. Given the global trend to legalize cannabis, this study is important as it highlights the effects of regular cannabis use on cortical dopamine function in high‐risk youth.

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Reference Region Modeling Approaches for Amphetamine Challenge Studies with [¹¹C]FLB 457 and PET

Cited by 71 publications

References 30 publications

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

A Perceptual Inference Mechanism for Hallucinations Linked to Striatal Dopamine

Stress‐induced cortical dopamine response is altered in subjects at clinical high risk for psychosis using cannabis

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Reference Region Modeling Approaches for Amphetamine Challenge Studies with [11C]FLB 457 and PET

Cited by 71 publications

References 30 publications

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

Characterization of [11C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

A Perceptual Inference Mechanism for Hallucinations Linked to Striatal Dopamine

Stress‐induced cortical dopamine response is altered in subjects at clinical high risk for psychosis using cannabis

Contact Info

Product

Resources

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Reference Region Modeling Approaches for Amphetamine Challenge Studies with [¹¹C]FLB 457 and PET