Kinetic modeling and occupancy measures of the norepinephrine transporters in baboons using single photon emission computed tomography with 123I‐INER

This study aims to investigate the pharmacokinetics of a recently developed radiotracer for imaging of the norepinephrine transporter (NET) in baboon brain, ¹²³I‐INER, using single photon emission computed tomography (SPECT). In addition, it also aims to determine NET occupancy by atomoxetine and reboxetine, two selective norepinephrine reuptake inhibitors, using ¹²³I‐INER in baboons. Baseline and preblocking studies with a high dose of atomoxetine (0.85 mg/kg) were conducted in three baboons using SPECT with ¹²³I‐INER administered as a bolus. Kinetic modeling analysis was investigated for different models, namely invasive and reference tissue models. Bolus plus constant infusion experiments with displacement at equilibrium using six different doses of atomoxetine (0.03–0.85 mg/kg) and four different doses of reboxetine (0.5–3.0 mg/kg) were carried out in several baboons to obtain occupancy measurements as a function of dose for the two NET selective drugs. Results showed that reference tissue models can be used to estimate binding potential values and occupancy measures of ¹²³I‐INER in different brain regions. In addition, the apparent volume of distribution was estimated by dividing concentration in tissue by the concentration in blood at 3 hours postinjection. After administration of atomoxetine or reboxetine, a dose‐dependent occupancy was observed in brain regions known to contain high densities of NET. In conclusion, pharmacokinetic properties of ¹²³I‐INER were successfully described, and obtained results may be used to simplify future data acquisition and image processing. Dose‐dependent NET occupancy for two selective norepinephrine reuptake inhibitors was successfully measured in vivo in baboon brain using SPECT and ¹²³I‐INER. Synapse, 2013. © 2012 Wiley Periodicals, Inc.     

¹²³I-NKJ64: a novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain

Dysregulation of noradrenergic function has been implicated in a variety of psychiatric and neurodegenerative disorders, including depression and Alzheimer's disease. The noradrenaline transporter (NAT) is a major target for antidepressant drugs, including reboxetine, a selective noradrenaline reuptake inhibitor. Therefore, the development of a radiotracer for imaging of the NAT is desirable. In this study, NKJ64, a novel iodinated analog of reboxetine, was radiolabeled and evaluated as a potential single photon emission computerized tomography (SPECT) radiotracer for imaging the NAT in brain. Biological evaluation of the novel radiotracer, ^123/125I‐NKJ64, was carried out in rats using: in vitro ligand binding assays; in vitro and ex vivo autoradiography; in vivo biodistribution studies and ex vivo pharmacological blocking studies. ¹²⁵I‐NKJ64 displayed saturable binding with high affinity for NAT in cortical homogenates (K_D = 4.82 ± 0.87 nM, mean ± SEM, n = 3). In vitro and ex vivo autoradiography showed the regional distribution of ¹²³I‐NKJ64 binding to be consistent with the known density of NAT in brain. Following i.v. injection there was rapid uptake of ¹²³I‐NKJ64 in brain, with maximum uptake of 2.93% ± 0.14% (mean ± SEM, n = 3) of the injected dose. The specific to nonspecific ratio (locus coeruleus:caudate putamen) of ¹²³I‐NKJ64 uptake measured by ex vivo autoradiography was 2.8 at 30 min post i.v. injection. The prior administration of reboxetine significantly reduced the accumulation of ¹²³I‐NKJ64 in the locus coeruleus (>50% blocking). The data indicate that further evaluation of ¹²³I‐NKJ64 in nonhuman primates is warranted in order to determine its utility as a SPECT radiotracer for imaging of NAT in brain. Synapse , 2011. © 2010 Wiley‐Liss, Inc.     

[125/123I]IPH: A radioiodinated analog of epibatidine for in vivo studies of nicotinic acetylcholine receptors

Tomographic imaging of central nicotinic acetylcholine receptors (nAChRs) via single photon emission computed tomography (SPECT) has been hampered by the lack of a radioligand with suitable in vivo binding characteristics. Therefore, a novel analog of epibatidine, (±)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane (IPH), labeled with [¹²⁵I] or [¹²³I] was evaluated as an in vivo marker of central nicotinic acetylcholine receptors (nAChRs). [¹²⁵I]IPH showed substantial brain penetration (4.2% of the injected dose at 30 min) and a cerebral biodistribution in mice consistent with the in vivo labeling of nAChRs (% injected dose/gram of thalamus, superior colliculi ≫ cerebellum). [¹²⁵I]IPH binding sites were shown to be saturable with unlabeled IPH (ED₅₀ approximately 1 μg/kg). The uptake of [¹²⁵I]IPH was blocked significantly by the nicotinic agonists, cytisine, lobeline, and (−)-nicotine, but not by the noncompetitive nAChR antagonist, mecamylamine. Antagonists of muscarinic (scopolamine), serotonin (ketanserin), and opioid (naloxone) receptors had no significant effect on [¹²⁵I]IPH binding. A preliminary SPECT imaging study with [¹²³I]IPH in a baboon showed [¹²³I]IPH to localize in nAChR-rich areas of brain (thalamus > frontal cortex > cerebellum). [¹²³I]IPH binding in baboon brain was also displaced (35–45% displacement) by a challenge dose of cytisine showing that a well-characterized nicotinic agonist effectively competes for [¹²³I]IPH binding sites. [¹²³I]IPH seems well suited for imaging studies of nAChRs and, to our knowledge, is the first SPECT agent that has allowed for the visualization of nAChRs in primate brain. Synapse 26:392–399, 1997. © 1997 Wiley-Liss Inc.     

Autoradiographic and SPECT imaging of cerebral opioid receptors with an iodine-123 labeled analogue of diprenorphine

The feasibility of imaging cerebral opioid receptors by single photon emission computed tomography (SPECT) has been established in baboon using a novel analog of diprenorphine (DPN) radiolabeled with iodine-123. The radioligand, [¹²³I]-O-IA-DPN (C6-O-[¹²³I]iodoallyl-DPN), was prepared in good yield (80%) with high radiochemical purity (>97%) and high specific radioactivity (>2,400 mCi/μmol). In ex vivo autoradiographic studies, with and without naltrexone blockade, [¹²³I]-O-IA-DPN specifically labeled opioid receptors throughout the mouse brain. Nonmetabolized radioligand accounted for >90% of the signal observed in extracts of whole mouse brain. SPECT imaging trials showed that [¹²³I]-O-IA-DPN selectively localized in regions of baboon brain known to have high densities of opioid receptors, such as striatum, thalamus, and temporal cortex. A much lower level of radioligand uptake and retention was noted for cerebellum, a region with few opioid binding sites. Pretreatment with naltrexone (6.5 μmol/kg) blocked [¹²³I]-O-IA-DPN binding in all brain regions. Using naltrexone blockade to define the nonspecific component for a given region of interest, total to nonspecific binding ratios increased linearly (r ≥ 0.98) over the SPECT study with maximal values for striatum (9.8), thalamus (7.1), and temporal cortex (6.9) reached at the last time point investigated (3.5 h). Specific binding for these regions, assessed as the difference between regional SPECT activity for the control and blocked states, proved irreversible over the observation period. By the end of the time course, specific [¹²³I]-O-IA-DPN binding was >85% of total radioactivity in regions rich in opioid receptors and 62% of total radioactivity in cerebellum. The aggregate data are consistent with visualization of multiple opioid receptor types. Thus, [¹²³I]-O-IA-DPN should prove useful for SPECT studies within the constraints imposed by a lack of innate selectivity for a single type of brain opioid receptor. Synapse 29:172–182, 1998. © 1998 Wiley-Liss, Inc.     

Regional brain imaging of vesicular acetylcholine transporter using o‐[125I]iodo‐trans‐decalinvesamicol as a new potential imaging probe

In this study, the regional rat brain distribution of radioiodinated o‐iodo‐trans‐decalinvesamicol ([¹²⁵I]OIDV) was determined in vivo to evaluate its potential as a single‐photon emission computed tomography (SPECT) imaging probe for vesicular acetylcholine transporter (VAChT). Following intravenous injection, [¹²⁵I]OIDV passed freely across the blood–brain barrier and accumulated in rat brain. The accumulation of [¹²⁵I]OIDV in rat brain was significantly reduced by coadministration of (+/?)‐vesamicol (0.125 µmol). In contrast, the coadministration of σ‐receptor ligands, such as (+)‐pentazocine (0.125 µmol) as a σ‐1 receptor ligand and (+)?3‐(3‐hydroxyphenyl)‐N‐propylpiperidine (0.125 µmol) as a σ‐1 and σ‐2 receptor ligands, barely affected the accumulation of [¹²⁵I]OIDV in rat brain. These findings in vivo were corroborated by autoradiographic analysis ex vivo. The authors found that the tracer binds with pharmacological selectivity to VAChT in rat brain and predicted that it may likewise serve in translational SPECT imaging studies of this marker in the integrity of cholinergic innervations. Synapse 68:107–113, 2014. © 2013 Wiley Periodicals, Inc.     

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.     

Head‐to‐head comparison of 18F‐FP‐CIT and 123I‐FP‐CIT for dopamine transporter imaging in patients with Parkinson's disease: A preliminary study

¹²³I‐FP‐CIT and ¹⁸F‐FP‐CIT are radiotracers which are widely used to diagnose Parkinson's disease (PD). However, to our knowledge, no studies to date have made head‐to‐head comparisons between ¹²³I‐FP‐CIT and ¹⁸F‐FP‐CIT. Therefore, in this study, ¹²³I‐FP‐CIT SPECT/CT was compared with ¹⁸F‐FP‐CIT PET/CT in the same cohort of subjects. Patients with PD and essential tremor (ET) underwent ¹²³I‐FP‐CIT SPECT/CT and ¹⁸F‐FP‐CIT PET/CT. Visual and semiquantitative analyses were conducted. The specific binding ratio (SBR) and putamen to caudate ratio (PCR) were compared between subjects who underwent ¹²³I‐FP‐CIT SPECT/CT and ¹⁸F‐FP‐CIT PET/CT. Visual analysis showed that the striatal uptake of both radiotracers was decreased in the PD group, whereas striatal uptake was intact in the ET group. The SBR between ¹²³I‐FP‐CIT SPECT/CT and ¹⁸F‐FP‐CIT PET/CT showed a positive correlation (r = .78, p < .01). However, the mean SBRs on ¹⁸F‐FP‐CIT PET/CT were higher than those on ¹²³I‐FP‐CIT SPECT/CT (2.19 ± .87 and 1.22 ± .49, respectively; p < .01). The PCRs in these two modalities were correlated with each other (r = .71, p < .01). The mean PCRs on ¹⁸F‐FP‐CIT PET/CT were not significantly higher than those on ¹²³I‐FP‐CIT SPECT/CT (1.31 ± .19 and 0.98 ± .06, respectively; p = .06). These preliminary results indicate that the uptake of both ¹²³I‐FP‐CIT and ¹⁸F‐FP‐CIT was decreased in the PD group when compared with the ET controls. Visual analyses using both methods did not affect the diagnostic accuracy in this study. However, semiquantitative analysis indicated a better contrast of ¹⁸F‐FP‐CIT PET/CT relative to ¹²³I‐FP‐CIT SPECT/CT.     

[123I]FP-CIT binds to the dopamine transporter as assessed by biodistribution studies in rats and SPECT studies in MPTP-lesioned monkeys

[¹²³I]FP-CIT (N-ω-fluoropropyl-2β-carbomethoxy-3β-{4-iodophenyl}tropane), a radioiodinated cocaine analogue, was evaluated as an agent for the in vivo labeling of dopamine (DA) transporters by biodistribution studies in rats and by single photon emission computed tomography (SPECT) studies in unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–lesioned monkeys. In rats, intravenous injection of [¹²³I]FP-CIT resulted in high accumulation of radioactivity in the striatum. Less pronounced uptake was seen in brain areas with high densities of serotonergic uptake sites. While striatal uptake of radioactivity after injection of [¹²³I]FP-CIT was displaced significantly by GBR12,909 but not by fluvoxamine, the opposite was observed in brain areas known to be rich of serotonin transporters. Monkeys which were unilaterally treated with neurotoxic doses of MPTP showed severe loss of striatal [¹²³I]FP-CIT uptake at the side of treatment. The results of this study indicate that [¹²³I]FP-CIT, although not being a selective radioligand, binds specifically to the striatal DA transporter in vivo and thus suggest that [¹²³I]FP-CIT promises to be a suitable radioligand for SPECT imaging of DA transporters in humans. Synapse 27:183–190, 1997. © 1997 Wiley-Liss, Inc.     

Single photon emission computed tomography experience with (S)‐5‐[123I]iodo‐3‐(2‐azetidinylmethoxy)pyridine in the living human brain of smokers and nonsmokers

(S)‐5‐[¹²³I]iodo‐3‐(2‐azetidinylmethoxy)pyridine (5‐[¹²³I]IA), a novel potent radioligand for high‐affinity α4β2* neuronal nicotinic acetylcholine receptors (nAChRs), provides a means to evaluate the density and the distribution of nAChRs in the living human brain. We sought in healthy adult smokers and nonsmokers to (1) evaluate the safety, tolerability, and efficacy of 5‐[¹²³I]IA in an open nonblind trial and (2) to estimate the density and the distribution of α₄β₂* nAChRs in the brain. Single photon emission computed tomography (SPECT) was performed for 5 h after the i.v. administration of ～0.001 μg/kg (～10 mCi) 5‐[¹²³I]IA. Blood pressure, heart rate, and neurobehavioral status were monitored before, during, and after the administration of 5‐[¹²³I]IA to 12 healthy adults (8 men and 4 women) (6 smokers and 6 nonsmokers) ranging in age from 19 to 46 years (mean = 28.25, standard deviation = 8.20). High plasma‐nicotine level was significantly associated with low 5‐[¹²³I]IA binding in: (1) the caudate head, the cerebellum, the cortex, and the putamen, utilizing both the Sign and Mann–Whitney U‐tests; (2) the fusiform gyrus, the hippocampus, the parahippocampus, and the pons utilizing the Mann–Whitney U‐test; and (3) the thalamus utilizing the Sign test. We conclude that 5‐[¹²³I]IA is a safe, well‐tolerated, and effective pharmacologic agent for human subjects to estimate high‐affinity α4/β2 nAChRs in the living human brain. Synapse 63:339–358, 2009. © 2009 Wiley‐Liss, Inc.     

Crossed cerebellocerebral diaschisis in patients with cerebellar stroke

Objectives– We performed single‐photon emission computed tomography (SPECT) to investigate crossed cerebellocerebral diaschisis (CCCD) in patients with cerebellar stroke. Material and methods– Fifteen patients with unilateral cerebellar stroke underwent SPECT of the brain with N‐isopropyl‐p‐[¹²³I] iodoamphetamine (¹²³I‐IMP). Regional cerebral blood flow (rCBF) was measured by the autoradiographic method. Regions of interest were defined in the cerebral cortex, striatum, thalamus and cerebellum to compare structures (contralateral to the cerebellar lesion) with counterparts ipsilateral to the stroke. Results– In the frontal and parietal cortices, especially the posterior superior frontal, anterior midfrontal, precentral, postcentral, and supramarginal areas, rCBF contralateral to the lesion was significantly lower than on the side of the lesion (showing CCCD). Conclusion – This CCCD phenomenon is important to be aware of in clinical reading of images.     

123I‐Ioflupane SPECT in the diagnosis of suspected psychogenic Parkinsonism

Psychogenic Parkinsonism (PsyP) can be clinically difficult to differentiate from Parkinson's disease (PD). Striatal dopamine transporter (DAT) imaging could be helpful in differentiating them. We performed ¹²³I‐Ioflupane single‐photon emission computed tomography (SPECT) in 9 patients with suspected PsyP. In 1 patient, ¹²³I‐Ioflupane SPECT disclosed bilateral decrease of striatal tracer uptake that indicated nigrostriatal degeneration. In this patient, a parkin gene mutation was detected. In the other 8 patients, ¹²³I‐Ioflupane SPECT was normal and supported the initial suspicion of PsyP. Normal DAT imaging supports the diagnosis of PsyP, whereas reduced striatal tracer uptake suggests an underlying neurodegenerative Parkinsonism and should encourage the search for additional causes for the syndrome. © 2006 Movement Disorder Society     

In vivo [123I]CNS‐1261 binding to D‐serine‐activated and MK801‐blocked NMDA receptors: A storage phosphor imaging study in rats

Disturbances of activity of the glutamatergic neurotransmitter system in the brain are present in many neuropsychiatric disorders. The N‐methyl‐D ‐aspartate (NMDA) receptor is the most abundant receptor of the glutamatergic system. In the neurodegenerative events of Alzheimer's disease, excessive activation of NMDA receptors may contribute to neuronal death. Inhibition of NMDA receptor activation may have neuroprotective effects and (semi)quantitative imaging of the activated system may help in the selection of patients for such inhibition therapies. In this study we evaluated [¹²³I]CNS‐1261 binding in the rat brain. This radiotracer binds in vivo to the MK801 binding site of activated NMDA receptors. To determine the optimal time point for ex vivo assessments after bolus injection [¹²³I]CNS‐1261 binding in rats, we performed a time course biodistribution study using dissection techniques. [¹²³I]CNS‐1261 binding was also studied in the rat brain using autoradiography by means of storage phosphor imaging, with prior facilitation of NMDA receptor activation by injection of the potent coagonist D ‐serine and after blocking of the NMDA receptor binding site by MK801 injection in D ‐serine pretreated rats. Measurements of [¹²³I]CNS‐1261 uptake matched the distribution of similar tracers for the MK801 binding site of the NMDA receptor and revealed an optimal time point of 2 h post injection for the assessment of tracer distribution in the rat brain. The blocking experiments indicated specific binding of [¹²³I]CNS‐1261 to NMDA receptors but also a considerable amount of nonspecific binding. Facilitation of NMDA receptor activation by D ‐serine did not result in an enhancement of binding of the radiotracer in the NMDA receptor‐rich rat hippocampus compared to the untreated group, as measured by autoradiography. In conclusion, our study has shown that [¹²³I]CNS‐1261 binding is influenced by NMDA receptor availability. However, high nonspecific binding limits quantification and small changes in receptor availability are unlikely to be detected. Synapse 63:557–564, 2009. © 2009 Wiley‐Liss, Inc.     

Abnormal distribution of GABAA receptors in brain of duchenne muscular dystrophy patients

Introduction: In this study we sought to: (1) determine the distribution of GABA_A receptors (GABA_A‐Rs) in the brain of Duchenne muscular dystrophy (DMD) patients; and (2) ascertain if the distribution pattern correlates with cognitive dysfunction. Methods: Fourteen DMD patients [young adult (n = 7, 18–25 years old) and older adult (n = 7, 30–37 years old) groups] and 16 age‐matched normal volunteers participated. GABA_A‐R distribution was assessed using ¹²³I‐IMZ‐SPECT. Neuropsychological assessments were performed using 3 different test batteries, the WAIS‐III, WMS‐R, and Wisconsin Card Sorting Test (WCST). Results: All DMD patients showed significant decline in ¹²³I‐IMZ uptake in the prefrontal cortex (P < 0.05). Although no differences were detected in the WAIS‐III and WMS‐R, the WCST scores of DMD patients (2.8 ± 1.9) were significantly lower (P < 0.01) than those of normal volunteers (5.4 ± 0.7). Both abnormalities were more pronounced in older adult patients. Conclusion: The findings demonstrate that DMD is accompanied by a reduction in the prefrontal cortex distribution of GABA_A‐Rs. Muscle Nerve 55 : 591–595, 2017     

Dopaminergic deficit is not the rule in orthostatic tremor

Involvement of the dopaminergic system in orthostatic tremor is controversial. The aim of this study was to detect possible dopaminergic denervation in primary orthostatic tremor (OT). Twelve consecutive patients with a firm diagnosis of primary orthostatic tremor were compared with age‐matched normal controls. All the patients had a neurological examination, surface polymyography, and quantification of striatal dopamine transporters with ¹²³I‐FP‐CIT SPECT imaging. There was no significant difference in ¹²³I‐FP‐CIT SPECT findings between controls and patients with OT. Longstanding primary orthostatic tremor is not necessarily associated with ¹²³I‐FP‐CIT SPECT abnormalities, as 8 of our patients had more than a 10‐year history of OT. Primary orthostatic tremor without dopaminergic denervation remains a valid entity, although representing only a subtype of high‐frequency OT. A new role may emerge for ¹²³I‐FP‐CIT SPECT in distinguishing between patients whose symptoms will be restricted to OT throughout the disease course and patients at an increased risk of developing PD. © 2008 Movement Disorder Society     

(123) I]FP-CIT-SPECT asymmetry index to differentiate Parkinson's disease from vascular parkinsonism

Contrafatto D, Mostile G, Nicoletti A, Dibilio V, Raciti L, Lanzafame S, Luca A, Distefano A, Zappia M. [¹²³I]FP‐CIT‐SPECT asymmetry index to differentiate Parkinson’s disease from vascular parkinsonism.
Acta Neurol Scand: 2012: 126: 12–16.
© 2011 John Wiley & Sons A/S. Objectives – Differential diagnosis between vascular parkinsonism (VP) and Parkinson’s Disease (PD) is often difficult, due to the overlap in clinical presentation and the lack of specificity at neuroimaging. Aim of the study was to identify a possible reliable marker at SPECT imaging useful to distinguish the two conditions. Material and methods – We studied 20 PD, 20 VP and 20 essential tremor (ET) patients as control group, who had undergone a cerebral [¹²³I] FP‐CIT SPECT. A semiquantitative analysis was performed on DaTSCAN SPECT imaging and to establish the degree of asymmetry of the ligand uptake the Striatal Asymmetry Index (SAI) was used. Results – The binding of the ligand in the most affected side resulted significantly lower in VP than in ET patients but higher compared to PD patients. SAI was significantly higher in PD compared to VP (P < 0.001) and ET (P < 0.001) groups. We found that a cut‐off of SAI greater than 14.08 could differentiate PD from VP with a 100% specificity and a 50% sensitivity. Conclusions – SAI detected using [¹²³I]FP‐CIT SPECT can be used to differentiate VP and PD with a good degree of certainty.     

Striatal dopamine transporter imaging correlates with depressive symptoms and tower of London task performance in Parkinson's disease

We studied whether the ¹²³I‐FP‐CIT uptake in the striatum correlates with depressive symptoms and cognitive performance in patients with Parkinson's disease (PD). Twenty patients with PD without major depression and/or dementia (mean age 61.7 ± 12.7 years) underwent the ¹²³I‐FP‐CIT SPECT. Depressive symptoms and cognitive performance were assessed in the ON state. The ratios of striatal to occipital binding for the entire striatum, putamina, and putamen to the caudate (put/caud) index were calculated in the basal ganglia. The association between neuropsychiatric measures and dopamine transporter (DAT) availability was calculated; multiple regression analysis was used to assess association with age and disease duration. We found significant correlations between Montgomery and Asberg Depression Rating Scale (MARDS) and Tower of London (TOL) task scores and ¹²³I‐FP‐CIT uptake in various striatal ROIs. Multiple regression analysis confirmed the significant relationship between TOL performance and put/caud ratio (P = 0.001) and to age (P = 0.001), and between MADRS and left striatal (P = 0.005) and putaminal DAT availability (P = 0.003). Our pilot study results demonstrate that imaging with ¹²³I‐FP‐CIT SPECT appears to be sensitive for detecting dopaminergic deficit associated with mild depressive symptoms and specific cognitive dysfunction in patients with PD, yet without a current depressive episode and/or dementia. © 2008 Movement Disorder Society     

A radioiodinated 7 α -O-iodoallyl diprenorphine for mapping opioid receptors

The aim of the current research has been to validate an original radioiodinated diprenorphine (DPN) derivative suitable for imaging studies of opioid receptors. [¹²⁵I]7α-O-iodoallyl diprenorphine (7α-O-IA-DPN) was prepared by radioiododestannylation and in vitro and in vivo opioid receptor binding assays were performed with CDF1 mouse brains.In vitro binding studies showed high affinity (K_i= 0.4 ± 0.2 nM) for mouse brain membranes. In vivo studies showed 63% specific binding. Ex vivo autoradiography of brain sections confirmed high uptake and retention of [¹²⁵I]7α- O -IA-DPN in regions rich in opioid receptors. This new radioiodinated DPN analogue appears to be a potential radioprobe for in vivo visualization of human cerebral opioid receptors with single photon emission computed tomography (SPECT).     

Altropane,a SPECT or PET imaging probe for dopamine neurons: II. distribution to dopamine-rich regions of primate brain

The dopamine transporter in brain, localized almost exclusively on dopamine neurons, is an effective window on dopamine neurons. SPECT or PET imaging of the transporter in brain requires selective imaging agents that display appropriate pharmacokinetic properties. We previously reported that [¹²⁵I]altropane ([¹²⁵I]IACFT,2β-carbomethoxy-3β-(4-fluorophenyl)-n- (1-iodoprop-1-en-3-yl)nortropane) bound with high affinity (Kd: 5.33 nM) to a single site on the dopamine transporter and was selective for dopamine over the serotonin transporter in homogenates of monkey striatum. To determine whether the selective binding of [¹²⁵I]altropane is reflected in its brain distribution, the in vitro and ex vivo distribution of [¹²⁵I]altropane in squirrel monkey (Saimiri sciureus) brain was determined by quantitative autoradiography of coronal brain sections. In vitro, [¹²⁵I]altropane (2 nM) distribution was discrete and was detectable primarily in the dopamine-rich putamen, caudate nucleus, and nucleus accumbens. The resulting putamen:cerebellum ratio exceeded 120:1 (n = 3). The selective in vitro binding of [¹²⁵I]altropane to the dopamine transporter, at concentrations approaching its Kd value (Kd: 5.33 nM, a single high affinity site), highlight its suitability for investigating the density of the dopamine transporter in various brain regions in vitro. Ex vivo autoradiography was conducted in monkeys to determine whether the brain distribution of [¹²⁵I]altropane in vitro was predictive of its brain distribution pattern after intravenous administration. Thirty minutes after intravenous injection, highest levels of [¹²⁵I]altropane (0.3 nmol/kg) were detected in the caudate-putamen and nucleus accumbens and lowest levels in the cerebellum and cortex. The putamen or caudate:cerebellum ratio was 7. SPECT imaging of the brain within 30 min of i.v. injection confirmed the rapid and selective accumulation of [¹²³I]altropane to the striatum. The selective binding of altropane to the dopamine-rich striatum within 30 min of i.v. administration indicates that it is uniquely suited for SPECT or PET imaging of the dopamine transporter and associated dopamine neurons. Synapse 29:105–115, 1998. © 1998 Wiley-Liss, Inc.     

In vivo SPECT imaging of 5-HT1A receptors with [123I] p-MPPI in nonhuman primates

The in vivo imaging of a novel iodinated phenylpiperazine derivative for 5-HT_1A receptors, [¹²³I]p-MPPI (4-(2′-methoxy-)phenyl-1-[2′-(n-2"-pyridinyl)-p-iodo-benzamido-]ethyl-piperazine), using single photon emission computed tomography (SPECT), was evaluated in nonhuman primates. After an i.v. injection, [¹²³I]p-MPPI penetrated the blood-brain barrier quickly and localized in brain regions where 5-HT_1A receptor density is high (hippocampus, frontal cortex, cingulate gyrus, entorhinal cortex). Maximum ratio of hippocampus to cerebellum was 3 to 1 at 50 min postinjection. The specific binding of the radioligand in the hippocampal region, an area rich in 5-HT_1A receptor density, was blocked by a chasing dose of (±) 8-OH-DPAT (2 mg/kg, i.v.) or non-radioactive p-MPPI (1 mg/kg, i.v.), whereas the regional distribution of [¹²³I]p-MPPI was unaffected by treatment with non 5-HT_1A agents, such as ketanserin. Ex vivo and in vitro autoradiographic studies using monkey brain further confirmed that the specific binding of [¹²³I]p-MPPI is associated with 5-HT_1A receptor sites. However, the initial attempt at [¹²³I]p-MPPI human imaging studies did not display specific localization of 5-HT_1A receptors. This discrepancy observed for [¹²³I]p-MPPI may be due to a dramatic difference in metabolic pathways between humans and monkeys. © 1996 Wiley-Liss, Inc.     

Microdialysis and SPECT measurements of amphetamine-induced dopamine release in nonhuman primates

The competition between endogenous transmitters and radiolabeled ligands for in vivo binding to neuroreceptors might provide a method to measure endogenous transmitter release in the living human brain with noninvasive techniques such as positron emission tomography (PET) or single photon emission computerized tomography (SPECT). In this study, we validated the measure of amphetamine-induced dopamine release with SPECT in nonhuman primates. Microdialysis experiments were conducted to establish the dose-response curve of amphetamine-induced dopamine release and to document how pretreatment with the dopamine depleter alpha-methyl-para-tyrosine (αMPT) affects this response. SPECT experiments were performed with two iodinated benzamides, [¹²³I]IBZM and [¹²³I]IBF, under sustained equilibrium condition. Both radio-tracers are specific D₂ antagonists, but the affinity of [¹²³I]IBZM (K_D = 0.4 nM) is lower than that of [¹²³I]IBF (K_D = 0.1 nM). With both tracers, we observed a prolonged reduction in binding to D₂ receptors following amphetamine injection. [₁₂₃I]IBZM binding to D₂ receptors was more affected than [¹²³I]IBF by high doses of amphetamine, indicating that a lower affinity increases the vulnerability of a tracer to endogenous competition. With [₁₂₃I]IBZM, we observed an excellent correlation between reduction of D₂ receptor binding measured with SPECT and peak dopamine release measured with microdialysis after various doses of amphetamine. Pretreatment with αMPT significantly reduced the effect of amphetamine on [₁₂₃I]IBZM binding to D₂ receptors, confirming that this effect was mediated by intrasynaptic dopamine release. Together, these results validate the use of this SPECT paradigm as a noninvasive measurement of intrasynaptic dopamine release in the living brain. Synapse 25:1–14, 1997. © 1997 Wiley-Liss, Inc.