SSRI antidepressants do not confound single photon emission computed tomography (SPECT) imaging studies using the α4β2 nicotinic acetylcholine receptor [123I]5‐I‐A85380 ligand: In vivo and in vitro evidence

Purpose: In clinical molecular imaging the interaction between antidepressant medication and SPECT ligands is a significant potential confound. This study measured nAChR availability, as determined by SPECT imaging, on and off selective serotonin reuptake inhibitors in first episode depressed patients. Methods: Five patients in their first episode of major depressive disorder (MDD) on a single SSRI underwent [¹²³I]5‐I‐A85380‐ SPECT neuroimaging prior to stopping their medication and again 6 weeks following medication cessation. Autoradiography of post mortem brain tissue with [¹²⁵I]5‐I‐A85380 in the presence or absence of four commonly prescribed antidepressants was also assessed. Results: SSRI antidepressants did not affect the relative binding availability of α4β2 nicotinic acetylcholine receptors for the [¹²³I]5‐I‐A85380 ligand in vivo. Radioligand binding in vitro was unaffected by a single, high pharmacological concentration of antidepressants. Conclusion: SPECT imaging studies using [¹²³I]5‐I‐A85380 to measure α4β2 nAChR availability in depressed patients are unlikely to be confounded to a major degree by concurrent antidepressant medication. Synapse 64:111–116, 2010. © 2009 Wiley‐Liss, Inc.     

Single photon emission computed tomography (SPECT) brain imaging using N,N,N'-trimethyl-N'-(2 hydroxy-3-methyl-5-123I-iodobenzyl)-1,3-propanediamine 2 HCl (HIPDM): intractable complex partial seizures

HIPDM-SPECT brain imaging was performed in four patients with intractable complex partial seizures (CPS). Three patients had an epileptogenic focus in one temporal lobe and underwent anterior temporal lobectomy. Interictal HIPDM-SPECT demonstrated decreased regional cerebral perfusion (rCP) in the epileptogenic area in only one patient, but ictal studies showed increased rCP in the epileptic foci of all three patients. In the fourth patient, interictal HIPDM-SPECT showed increased rCP in the area of epileptogenic focus; when antiepileptic medication was taken, rCP decreased. HIPDM-SPECT brain imaging is useful for localizing epileptogenic foci in CPS.     

[11C]β-CIT-FE,a radioligand for quantitation of the dopamine transporter in the living brain using positron emission tomography

The cocaine analogue β-CIT-FE (N-(2-fluoroethyl)-2β-carbomethoxy-3β-(4-iodophenyl)nortropane) was labeled with ¹¹C for positron emission tomography (PET) studies of the dopamine transporter. After intravenous administration to a cynomolgus monkey, [¹¹C]β-CIT-FE accumulated in the striatum with a striatum-to-cerebellum ratio of about 9 after 60 min. Pseudoequilibrium of specific [¹¹C]β-CIT-FE binding in the striatum was obtained within 30–50 min. The radioactivity ratios of the thalamus to the cerebellum and the neocortex to the cerebellum were about 2 and 1.5, respectively. In displacement and pretreatment experiments, radioactivity in the striatum but not in the cerebellum was reduced after injection of β-CIT or the dopamine transporter inhibitor GBR 12909, indicating that striatal radioactivity following injection of [¹¹C]β-CIT-FE represents reversible binding to dopamine transporter sites. After displacement or pretreatment with cocaine there was a marked effect not only in the striatum but also in the thalamus and neocortex. [¹¹C]β-CIT-FE has potential as a useful PET radioligand for quantitation of the dopamine transporter in the primate brain in vivo. © 1996 Wiley-Liss, Inc.     

The dopamine D1 receptor agonist (S)‐[11C]N‐methyl‐NNC 01‐0259 is not sensitive to changes in dopamine concentration—a positron emission tomography examination in the monkey brain

Dopamine D₂ receptor positron emission tomography (PET) radioligands have proven useful for indirect assessment of the endogenous dopamine concentration in the living brain. On the contrary, dopamine D₁ receptor antagonist radioligands have shown no sensitivity to changes in the dopamine concentration. A recent approach to enhance the sensitivity of radioligands to the dopamine concentration has been the development of dopamine D₂ receptor agonist radioligands. The aim of this study was to evaluate the dopamine sensitivity of a dopamine D₁ receptor agonist radioligand. For this purpose, we developed (S)‐[¹¹C]N‐methyl‐NNC 01–0259 ((S)‐[¹¹C] 1 ) and characterized the receptor binding of (S)‐[¹¹C] 1 using in vitro receptor binding assays and in vivo PET measurements in monkeys. In vitro, both enantiomers of 1 were partial dopamine D₁ receptor agonists, with (S)‐ 1 having a 10–50 times higher affinity than (R)‐ 1 . PET studies in monkey confirmed the stereoselectivity of [¹¹C] 1 in vivo. In monkey, administration of the dopamine D₁‐like receptor antagonist (R)‐(+)‐SCH 23390 decreased the striatal binding potential of (S)‐[¹¹C] 1 by 97%, but administration of the dopamine concentration enhancer d ‐amphetamine did not affect (S)‐[¹¹C] 1 binding. We conclude that the agonist (S)‐[¹¹C] 1 provides specific binding to dopamine D₁‐like receptors, possibly representing binding to the high‐affinity state of the receptors. The partial dopamine D₁ receptor agonist radioligand has, however, no enhanced sensitivity to endogenous dopamine concentrations in comparison with antagonist radioligands. Synapse 67:586–595, 2013. © 2013 Wiley Periodicals, Inc.     

Differential influence of propofol and isoflurane anesthesia in a non‐human primate on the brain kinetics and binding of [18F]DPA‐714, a positron emission tomography imaging marker of glial activation

Translocator protein 18 kDa (TSPO) expression at the mitochondrial membrane of glial cells is related to glial activation. TSPO radioligands such as [¹⁸F]DPA‐714 are useful for the non‐invasive study of neuroimmune processes using positron emission tomography (PET). Anesthetic agents were shown to impact mitochondrial function and may influence [¹⁸F]DPA‐714 binding parameters and PET kinetics. [¹⁸F]DPA‐714 PET imaging was performed in Papio anubis baboons anesthetized using either intravenous propofol (n = 3) or inhaled isoflurane (n = 3). Brain kinetics and metabolite‐corrected input function were measured to estimate [¹⁸F]DPA‐714 brain distribution (V_T). Displacement experiments were performed using PK11195 (1.5 mg/kg). In vitro [¹⁸F]DPA‐714 binding experiments were performed using baboon brain tissue in the absence and presence of tested anesthetics. Brain radioactivity peaked higher in isoflurane‐anesthetized animals compared with propofol (SUV_max = 2.7 ± 0.5 vs. 1.3 ± 0.2, respectively) but was not different after 30 min. Brain V_T was not different under propofol and isoflurane. Displacement resulted in a 35.8 ± 8.4% decrease of brain radioactivity under propofol but not under isoflurane (0.1 ± 7.0%). In vitro, the presence of propofol increased TSPO density and dramatically reduced its affinity for [¹⁸F]DPA‐714 compared with control. This in vitro effect was not significant with isoflurane. Exposure to propofol and isoflurane differentially influences TSPO interaction with its specific radioligand [¹⁸F]DPA‐714 with subsequent impact on its tissue kinetics and specific binding estimated in vivo using PET. Therefore, the choice of anesthetics and their potential influence on PET data should be considered for the design of imaging studies using TSPO radioligands, especially in a translational research context.     

PET imaging of the effects of age and cocaine on the norepinephrine transporter in the human brain using (S,S)‐[11C]O‐methylreboxetine and HRRT

Objectives: The role of the norepinephrine transporter (NET) in cocaine dependence has never been demonstrated via in vivo imaging due to the lack of suitable NET radioligands. Here we report our preliminary studies evaluting the NET in individuals with cocaine dependence (COC) in comparison to healthy controls (HC) using (S,S)‐[¹¹C]methylreboxetine ([¹¹C]MRB), the most promising C‐11 labeled positron‐emission tomography (PET) radioligand for NET developed to date. Methods: Twenty two human volunteers (10 COC and 12 HC) underwent dynamic ¹¹C‐MRB‐PET acquisition using a High Resolution Research Tomograph (HRRT). Binding potential (BP_ND) parametric images were computed using the simplified reference tissue model (SRTM2) with occipital cortex as reference region. BP_ND values were compared between the two groups. Results: Locus coeruleus (LC), hypothalamus, and pulvinar showed a significant inverse correlation with age among HC (age range = 25–54 years; P = 0.04, 0.009, 0.03 respectively). The BP_ND was significantly increased in thalamus (27%; P < 0.02) and dorsomedial thalamic nuclei (30%; P < 0.03) in COC as compared to HC. Upon age normalization, the upregulation of NET in COC also reached significance in LC (63%, P < 0.01) and pulvinar (55%, P < 0.02) regions. Conclusion: Our results suggest that (a) brain NET concentration declines with age in HC, and (b) there is a significant upregulation of NET in thalamus and dorsomedial thalamic nucleus in COC as compared to HC. Our results also suggest that the use of [¹¹C]MRB and HRRT provides an effective strategy for studying alterations of the NET system in humans. Synapse 64:30–38, 2010. © 2009 Wiley‐Liss, Inc.