D2 Receptor Imaging Research Articles

Radiosynthesis and Evaluation of [11C]-(+)-4-Propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol as a Potential Radiotracer for in Vivo Imaging of the Dopamine D2 High-Affinity State with Positron Emission Tomography

In vivo imaging of dopamine D2 receptors with agonist (as opposed to the more commonly employed antagonist) radiotracers could provide important information on the high-affinity (functional) state of the D2 receptor in illnesses such as schizophrenia, movement disorders, and addictions. We report here the radiosynthesis and evaluation of the potent D2 agonist (+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol, (+)-3, labeled with carbon-11, as a potential radiotracer for imaging the high-affinity state of dopamine D2 receptors with positron emission tomography (PET). [(11)C]-(+)-3 was reliably synthesized in the quantities and at the specific activities and radiochemical purities required for human PET studies. Ex vivo biodistribution studies in rat brain demonstrated that [(11)C]-(+)-3 crossed the blood-brain barrier readily and had an appropriate regional brain distribution for a radiotracer that maps dopamine D2 receptors. The binding of [(11)C]-(+)-3 was saturable and demonstrated an excellent signal-to-noise ratio as measured by its striatum-to-cerebellum ratio of 5.6, 60 min postinjection. The binding was highly stereospecific, and blocking and displacement studies were consistent with selective and specific binding to the dopamine D2 receptors. Further, [(11)C]-(+)-3 showed marked and appropriate sensitivity to both increases and decreases in the levels of endogenous dopamine. Brain radioactive metabolite and physicochemical measurements are in full accord with the desired properties of a neuroreceptor imaging agent for PET. All of the above, coupled with the documented full D2 agonistic properties of (+)-3, strongly indicate that [(11)C]-(+)-3 is a leading candidate radiotracer for the imaging of the dopamine D2 high-affinity state using PET in human subjects.

Biodistribution and radiation dosimetry of [11C]raclopride in healthy volunteers

This study reports on the whole-body biodistribution and radiation dosimetry of [11C]raclopride, a dopamine D2 receptor antagonist. In three healthy male volunteers, whole-body scans were performed up to 2 h following i.v. injection of 320+/-65 MBq [11C]raclopride. Transmission scans (3 min per step, eight or nine steps according to the height of the subject) in 2D mode were used for subsequent attenuation correction of emission scans. Emission scans (1 min per step, eight or nine steps) were acquired over 2 h. Venous blood samples and urine were collected up to 2 h after injection of the radiotracer. For each subject, the percentage of injected activity measured in regions of interest over brain, intestine, lungs, kidneys and liver was fitted to a mono-exponential model, as an uptake phase followed by a mono-exponential washout, for urinary bladder to generate time-activity curves. Using the MIRD method, several source organs were considered in estimating residence time and mean effective radiation absorbed doses. Blood pressure and ECG findings remained unchanged after tracer injection. The analysed blood and urine pharmacological parameters did not change significantly after [(11)C]raclopride injection. The primary routes of clearance were renal and intestinal. Ten minutes after injection, high activities were observed in the gall-bladder, kidneys and liver. High activity was observed in the gall-bladder during the whole study. The kidneys, urinary bladder wall, liver and gall-bladder received the highest absorbed doses. The average effective dose of [11C]raclopride was estimated to be 6.7+/-0.4 microSv/MBq. The amount of [11C]raclopride required for adequate dopamine D2 receptor imaging results in an acceptable effective dose equivalent, permitting two or three repeated clinical PET imaging studies, with the injection of 222 MBq for each study.

Imaging of dopamine transporters and D2 receptors in vascular parkinsonism: a report of four cases

The role of nuclear medicine imaging in the diagnosis of vascular parkinsonism (VP) has been addressed by only few studies up to now. Most previous reports suggest no or only mild impairment of DAT and D2 receptors in VP. In contrast, in four patients with VP, reported here, the combined DAT and D2 receptor SPECT showed highly unusual changes in the pre- and/or postsynaptic dopaminergic system. The possible value of combined DAT/D2 receptor SPECT imaging should be investigated by future prospective studies.

Imaging of dopamine transporters and D2 receptors in patients with Parkinson?s disease and multiple system atrophy

The aim of this study was to ascertain whether combined presynaptic and postsynaptic dopaminergic single-photon emission computed tomography (SPECT) scanning is useful for differentiation between patients with idiopathic Parkinson's disease (IPD), patients with multiple system atrophy of the striatonigral type (MSA) and healthy subjects. SPECT measurements of the dopamine transporter (DAT) were done with 123I-beta-CIT, while for determination of the dopamine D2-like receptors (D2), 123I-epidepride was used. Clinical evaluation and SPECT scans were carried out in 14 patients with IPD, eight patients with MSA and 11 healthy age-matched control subjects. Putaminal DAT binding was reduced to 32% of control values in IPD and to 19% of control values in MSA . Significantly higher striatal asymmetry in DAT binding was found in MSA than in controls, but IPD patients had significantly higher asymmetry than MSA patients. Striatal D2 binding did not differ significantly between patients and healthy controls but the ratio between caudate DAT and D2 binding was significantly higher in patients with IPD than in those with MSA, even when disease severity was taken into account. Patients with reduced striatal 123I-beta-CIT binding and a side-to-side difference greater than 15% are likely to suffer from IPD. Patients with reduced striatal 123I-beta-CIT binding and a side-to-side difference of between 5% and 15% are more likely to have MSA. 123I-epidepride SPECT measurements may add further diagnostic information, since the ratio between DAT and D2 receptor binding is significantly higher in IPD than in MSA.

PET imaging of dopamine D1 and D2 receptors in patients treated with clozapine, olanzapine, quetiapine, or risperidone

PET imaging of dopamine D1 and D2 receptors in patients treated with clozapine, olanzapine, quetiapine, or risperidone

The Discovery of Epidepride and Its Analogs as High-Affinity Radioligands for Imaging Extrastriatal Dopamine D2 Receptors in Human Brain

[(123)I]Epidepride, [(18)F]fallypride, and [(76)Br]isoremoxipride (FLB-457) and their corresponding [(11)C]labeled derivatives belong to a class of high-affinity radioligands for SPECT or PET imaging of dopamine D(2) receptors in the human brain. In contrast to previously used imaging agents, these ligands are capable of identifying extrastriatal dopamine D(2) receptors. The design of these substituted benzamides derive its origin from the atypical antipsychotic agent, remoxipride. Starting in the late 1970's, halogenated analogs of (S)-sulpiride were evaluated in binding assays and behavioral studies, leading to the discovery of remoxipride. Remoxipride was 10 times weaker than sulpiride in vitro but 50 times more potent in vivo. Search for a putative active metabolite of remoxipride led to the discovery of raclopride and eticlopride, the former becoming a useful radioligand as tritium or carbon-11 labeled form for receptor binding and PET studies, respectively. In the US, the mono-iodine analog of raclopride, [(123)I]iodobenzamide (IBZM), was found to have moderate putamen-to-cerebellum ratio in rat and human brain. Continued search for metabolites of remoxipride led to the discovery of its 3,6-dihydroxy derivative, NCQ-344, with an extremely potent in vivo activity in the rat. SAR studies of the metabolites of remoxipride led to the discovery of the 3-methoxy isomer, isoremoxipride (FLB-457) and its corresponding 6-hydroxy analog, FLB-463, both having affinities for the dopamine D(2) receptor in the 20-30 pM range. Later, the 5-[(123)I]iodo analog of FLB-463, [(123)I]ioxipride ([(123)I]NCQ-298), became a potential SPECT imaging agent. In the mean time, the deshydroxy analog of IBZM, [(125)I]iodopride, showed binding potential in the rat similar to [(125)I]IBZM. Epidepride was designed by combining the structure of isoremoxipride with that of iodopride. In 1988, epidepride was independently prepared and radiolabeled in three separate laboratories in Stockholm, Berkeley, and Nashville. Evaluation of seven [(125)I]iodine substituted analogs of raclopride, including IBZM, revealed the unusual high striatum-to-cerebellum ratio of 234 of [(125)I]epidepride in the rat. Subsequent SPECT images with [(123)I]epidepride demonstrated its ability to identify extrastriatal dopamine D(2) receptors in the human brain. Exploration of the structure of epidepride confirmed its exceptional properties, to be exceeded only by its N-allyl homolog, [(125)I]nalepride. The design by others of a series of potent 5-(3-[(18)F]fluoropropyl) substituted analogs of epidepride for PET imaging, lead to the discovery of [(18)F]fallypride. By elucidating the role of lipophilicity in the substituted benzamides, the excellent imaging characteristics of [(11)C]/[(123)I]epidepride, [(11)C]/[(76)Br]isoremoxipride and [(18)F]fallypride, could not only be explained but predicted with remarkable accuracy. By using the inverse product of the receptor affinity (K(D)), and the apparent partition constant of the radioligand (P((7.4))), estimates of maximal binding potential of any radioligand for imaging of any neurotransmitter receptor or transporter site seem possible.

SPECT and PET imaging of the dopaminergic system in Parkinson's disease.

This paper gives an overview of the clinical importance of SPECT and PET imaging of the dopaminergic system in the differential diagnosis and for the determination of the progression rate of Parkinson's disease (PD). D2 receptor imaging can help to differentiate multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) from PD. In patients treated with neuroleptics it is possible to determine the rate of striatal D2 receptor blockade using this technique. This occupancy rate parallels the occurrence of parkinsonian side effects. Its measurement helps in the selection of newer atypical neuroleptics, which can be used to treat drug-induced psychosis in PD because they do not aggravate parkinsonian symptoms. Imaging of dopaminergic neurons with [123I]beta-CIT SPECT or [18F]DOPA PET is a way to visualize and quantify the nigrostriatal dopaminergic lesion in PD. Findings correlate with clinical rating scales and demonstrate the feasibility of detecting the preclinical lesion in patients with hemiparkinson or familial PD. [123I]beta-CIT SPECT can easily distinguish patients with essential tremor and patients with "lower body parkinsonism" due to a subcortical vascular encephalopathy. MSA and PSP cannot be separated from PD with this method alone. Longitudinal studies with [123I]beta-CIT SPECT and [18F]DOPA PET can quantify the progression rate in PD. SPECT results from our own group show a low rate of progression in patients with a long duration of disease and a more marked progression rate in patients with shorter disease duration. In the former group regions in the striatum with higher beta-CIT binding at the time of the first SPECT scan decline faster than regions with lower binding. These findings suggest a curvilinear course of progression which starts at different time points in different striatal regions and which levels off after several years of disease duration. These findings are in line with data from PET studies and underline the importance of an early start of neuroprotective strategies. Preliminary data from PET and SPECT studies in early PD suggest that dopamine agonists might have a slight neuroprotective effect and might slow down the rate of progression of the disease.

Metabolism of [123I]epidepride may affect brain dopamine D2 receptor imaging with single-photon emission tomography.

Iodine-123 labelled epidepride is a novel radiopharmaceutical for the study of cerebral dopamine D2 receptors using single-photon emission tomography (SPET). A lipophilic labelled metabolite of [123I]epidepride which may enter the brain and hamper the quantitation of receptors has been observed in human plasma. In the present study, gradient high-performance liquid chromatography (HPLC) was used to investigate the plasma concentration of the lipophilic labelled metabolite and its correlation to SPET imaging of striatal dopamine D2 receptors. A linear regression fit showed a negative correlation between the amount of the lipophilic labelled metabolite and the striatum to cerebellum ratio (n=16, R=-0.58, P<0.02), suggesting that plasma metabolite analysis is essential when imaging dopamine D2 receptors with SPET using [123I]epidepride.

Malignant Prolactinoma Discovered by D2 Receptor Imaging

Malignant Prolactinoma Discovered by D2 Receptor Imaging

Iodine-123 iodobenzofuran (I-123 IBF) SPECT in patients with parkinsonism.

I-123 IBF is a dopaminergic antagonist which is suitable for SPECT imaging of D2 receptors. The purpose of this study is to evaluate the potential usefulness of semi-quantitative parameters obtained from brain SPECT data of I-123 IBF for differential diagnosis in patients with parkinsonism (PN). Subjects were 10 patients with PN: 2 patients with striato-nigral degeneration (SND), 5 patients with Parkinson's disease (PD), 2 patients with progressive supranuclear palsy (PSP) and one patient with olivo-ponto-cerebellar atrophy (OPCA). The data were acquired with a triple-head gamma camera at 2 hours after intravenous injection of 167 MBq of I-123 IBF. Transverse images were reconstructed by means of filtered backprojection, and attenuation correction was performed by Chang's method (mu = 0.08). The basal ganglia-to-frontal cortex ratio (GFR) and the basal ganglia-to-occipital cortex ratio(GOR) on slices of 5 different thicknesses were calculated. The GFR and GOR were lower in the SND group than in the other disease groups in all slices with different thicknesses (7.2 mm, 14.4 mm, 21.6 mm, 28.8 mm and 43.2 mm). The semiquantitative parameters (GFR and GOR) obtained from brain SPECT data at 2 hours after intravenous injection of I-123 IBF may be useful for differential diagnosis in patients with PN.

PET Imaging of Dopamine D2 Receptors with [18F]Fluoroclebopride in Monkeys: Effects of Isoflurane- and Ketamine-Induced Anesthesia

The purpose of the present study was to determine whether positron emission tomography (PET) studies in monkeys with the dopamine (DA) D2 receptor ligand [18F]fluoroclebopride (FCP) would be significantly influenced by anesthetic induction with isoflurane (∼5.0%) compared to induction with 10 mg/kg ketamine. Five experimentally-naive adult male cynomolgus monkeys (Macaca fascicularis) were trained to sit calmly in a primate restraint chair. Before the first PET scan, each monkey was anesthetized, by mask, with isoflurane. After complete sedation, the monkey was intubated and anesthesia was maintained throughout the PET study by isoflurane (∼1.5%). At least 1 month later, a second PET study was conducted in which anesthesia was induced with ketamine and maintained by isoflurane (∼1.5%). Irrespective of induction anesthetic, there was a high uptake of [18F]FCP and a linear rate of washout from the basal ganglia for all monkeys. There were also no differences in time to peak uptake (∼25 min), in clearance half-life (t1/2= 140–164 min) or in D2 binding (distribution volume ratios of 2.48 vs. 2.50). These results indicate that induction anesthetic did not differentially affect D2 binding of [18F]FCP in monkeys. Furthermore, the low variability between studies indicates that [18F]FCP is an excellent ligand for longitudinal studies of D2 receptors in nonhuman primates.

Imaging D2 Receptor Occupancy by Endogenous Dopamine in Humans

The impact of endogenous dopamine on in vivo measurement of D2 receptors in humans was evaluated with single photon emission computerized tomography (SPECT), by comparing the binding potential (BP) of the selective D2 radiotracer [123I]IBZM before and after acute dopamine depletion. Dopamine depletion was achieved by administration of the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT), given orally at a dose of 1 g every six hours for two days. AMPT increased [123I]IBZM BP by 28 ± 16% (±SD, n = 9). Experiments in rodents suggested that this effect was due to removal of endogenous dopamine rather than D2 receptor upregulation. Synaptic dopamine concentration was estimated as 45 ± 25 nM, in agreement with values reported in rodents. The amplitude and the variability of the AMPT effect suggested that competition by endogenous dopamine introduces a significant error in measurement of D2 receptors in vivo with positron emission tomography (PET) or SPECT. However, these results also imply that D2 receptor imaging coupled with acute dopamine depletion might provide estimates of synaptic dopamine concentration in the living human brain.

Striatal and extrastriatal imaging of dopamine D2 receptors in the living human brain with [123I]epidepride single-photon emission tomography.

The iodine-123 labelled ligand benzamide epidepride was evaluated as a probe for in vivo imaging of striatal and extrastriatal dopamine D2 receptor sites in the human brain. Four healthy males were imaged with a high-resolution single-photon emission tomography scanner. Striatal radioactivity peaked at 3 h after injection. The specific binding in the striatum was 0.91+/-0.03 at 3 h and this ratio steadily increased with time. Extrastriatal radioactivity was highest in the thalamus, in the midbrain and in the temporal cortex, and peaked at 45-60 min after injection of tracer. A smaller amount of radioactivity was found in the parietal, frontal and occipital cortices. Two radioactive metabolites were observed, of which one was more lipophilic than the parent compound. The radiation burden to the patient was 0.035 mSv/MBq (effective dose equivalent). The preliminary results showed that [123I]epidepride can be used for imaging striatal and extrastriatal dopamine D2 receptor sites in the living human brain.

D2-receptor imaging with [123I]IBZM and single photon emission tomography in psychiatry: a survey of current status.

D2-dopamine receptors can be visualized in the human brain in vivo by Single Photon Emission Tomography (SPECT) and the radiolabeled benzamide [123I]IBZM. The present paper reviews the current status of this type of functional brain imaging with respect to basic methodological aspects, data analysis and quantification. The results from published clinical studies in different psychiatric patient populations and normal controls with [123I]IBZM are reviewed. [123I]IBZM-SPECT is a powerful tool for the investigation of D2-dopamine receptor status in psychiatric disorders, different types of drug treatment as well as therapeutic and side effects of pharmacologic agents. However, there still is a need for standardized imaging times and image-processing procedures. Advantages and disadvantages of SPECT with special regard to Positron Emission Tomography (PET) are also discussed.

Validation of quantitative brain dopamine D2 receptor imaging with a conventional single-head SPET camera

Phantom measurements were performed with a conventional single-head single-photon emission tomography (SPET) camera in order to validate the relevance of the basal ganglia/frontal cortex iodine-123 iodobenzamide (IBZM) uptake ratios measured in patients. Inside a cylindrical phantom (diameter 22 cm), two cylinders with a diameter of 3.3 cm were inserted. The activity concentrations of the cylinders ranged from 6.0 to 22.6 kBq/ml and the cylinder/background activity ratios varied from 1.4 to 3.8. From reconstructed SPET images the cylinder/background activity ratios were calculated using three different regions of interest (ROIs). A linear relationship between the measured activity ratio and the true activity ratio was obtained. In patient studies, basal ganglia/frontal cortex IBZM uptake ratios determined from the reconstructed slices using attenuation correction prior to reconstruction were 1.30 +/- 0.03 in idiopathic Parkinson's disease (n = 9), 1.33 +/- 0.09 in infantile and juvenile neuronal ceroid lipofuscinosis (n = 7) and 1.34 +/- 0.05 in narcolepsy (n = 8). Patients with Huntington's disease had significantly lower ratios (1.09 +/- 0.04, n = 5). The corrected basal ganglia/frontal cortex ratios, determined using linear regression, were about 80% higher. The use of dural-window scatter correction increased the measured ratios by about 10%. Although comprehensive correction methods can further improve the resolution in SPET images, the resolution of the SPET system used by us (1.5-2 cm) will determine what is achievable in basal ganglia D2 receptor imaging.

Dopamine D2 receptor SPECT imaging: basic in vivo characteristics and clinical applications of 123I-IBZM in humans.

The purposes of this study are to evaluate the utility of kit formulation, the basic in vivo characteristics, and clinical usefulness of dopamine D2 receptor imaging with 123I-(S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrodinyl)m ethyl]- benzamide (123I-IBZM). We studied 22 normal controls, 3 early symptomatic Huntington's disease patients, and 1 patient with visual hallucination on and off neuroleptics. 123I-IBZM could be conveniently prepared with a high degree of purity from a kit, but with relatively low radiochemical yield. We demonstrated 123I-IBZM receptor binding equilibrium by performing serial SPECT scanning in a normal volunteer. The basal ganglia/frontal cortex (BG/FC) ratios plateaued after the specific binding reached equilibrium approximately 60 minutes after injection. The BG/FC ratio declined significantly with age. The ratios for the Huntington's disease patients were significantly lower than those for normal controls. The images of the patient off neuroleptic therapy showed dramatically increased BG activity compared with those obtained while on therapy. The BG/FC ratio provides an estimate of Bmax/Kd and hence the receptor density. It appears important to perform SPECT early in the equilibrium phase and at a fixed time after injection to obtain significantly high signal to noise ratios. 123I-IBZM is an ideal tracer for SPECT including a rotating gamma camera type which can provide estimates of the receptor density objectively by calculating the BG/FC ratio, and is a promising agent for the investigation of dopamine D2 receptors in clinical conditions.

Dopamine D2 receptor imaging with SPECT using IBZM in 16 patients with Parkinson disease.

The striatal D2 receptor was investigated for variability of behavior in 16 patients with Parkinson disease by means of SPECT using 123I-IBZM, a recently synthesized radioligand with high affinity and specificity for this type of receptor. All the patients underwent routine laboratory tests, EEG and cranial CT scanning as well as SPECT. To ensure accurate clinical assessment we used the Hoehn and Yahr, and Webster scales, NUDS and Mini Mental State examination. Our preliminary data indicate: increased uptake by the striatal dopamine receptor in untreated patients with early PD compared with controls (striatum/cerebellum ratio of 1.77 +/- 0.12 vs 1.59 +/- 0.13); a slight but significant lowering of D2 receptor binding when L-Dopa is started (1.49 +/- 0.09); low D2 uptake values in the more severely affected patients; absence of asymmetries in hemiparkinsonism.

SPECT imaging of D2 receptors in depression

The basal ganglia have received increasing attention with regard to their role in time pacing, motor function and other components of cognition. The aim of this study was to test whether the finer the motor activity and/or time perception performance were, the higher the striatal dopamine D2 binding would be. Single photon emission computed tomography (SPECT) with [123I]iodobenzamide (IBZM) was performed to measure striatal D2 receptor densities. A battery of neuropsychological tests, including the Wisconsin Card Sorting Test (WCST), the finger tapping test (FTT), and an attention test, was performed by patients with schizophrenia. Results indicated a strong correlation between the FTT score and striatal D2 receptor binding. Neuroleptic dosage plays an important role in the relationship between cognitive tasks and striatal dopamine receptor densities. In addition, the striatal D2 receptor density is more significantly correlated with attentional tests that consider the time effect than those that do not. Among the three tests performed, the WCST was least significantly correlated with striatal D2 receptor densities. A decrease in striatal dopamine D2 receptor density seems to be associated with impaired performance on optimal timing tasks and motor processing in patients with schizophrenia.

102. Dopamine D2-receptor imaging with 123I-IBZM SPECT for the differential diagnosis of Parkinsonism

Verhoeff, N. P.L.G.1; Speelman, J. D.2; Kuiper, M. A.3; Kapucu, O.1; van Royen, E. A.1; Janssen, A. G.M.4; Wolters, E. Ch.M.J.3 Author Information

123 I‐iodobenzamide‐SPECT predicts dopaminergic responsiveness in patients with de novo parkinsonism

We used 123I-iodobenzamide-single photon emission computed tomography (IBZM-SPECT) in a prospective study to investigate 38 patients with parkinsonism (Hoehn and Yahr stage I to III) not previously treated with dopamimetic drugs. Thirty-four patients only showed symptoms of Parkinson's disease, and four patients showed, in addition, subtle clinical signs of progressive supranuclear palsy or multisystem atrophy. IBZM is a dopamine D2 receptor antagonist detectable by SPECT. We compared IBZM-SPECT results with clinical response to subcutaneous injections of the D1/D2 dopamine receptor agonist apomorphine (38 patients) and long-term dopamimetic therapy (31 patients). IBZM-SPECT results predicted a positive or negative response to apomorphine in 30 of 34 patients (apomorphine response in four patients was equivocal) and response to dopamimetic therapy in 27 of 31 patients. Thus, imaging of dopamine D2 receptors using readily available IBZM-SPECT seems to distinguish between L-dopa-responsive (most likely Parkinson's disease of Lewy body type) and L-dopa-unresponsive parkinsonism in patients not previously treated with dopamimetic drugs.