Filip Dumont

Prefrontal 5-HT2a receptor binding index, hopelessness and personality characteristics in attempted suicide

BACKGROUND Depression, hopelessness, impaired problem solving capacities and deficient serotonergic functions have been identified as major causes of suicidal behaviour. In general, the relation between biological markers of attempted suicide and psychological functions has been investigated using indirect peripheral markers of, e.g. the serotonergic system. Recently, functional neuroimaging techniques with radioligands allow direct in vivo assessment of the neurobiological status of the central nervous system. METHODS We studied the binding index of serotonin-(2a) (5-HT(2a)) receptors in the frontal cortex of attempted suicide patients (n=9) and normal controls (n=13) using [123I]5-I-R91150, a highly selective 5-HT(2a) receptor ligand. Moreover, we measured personality characteristics (using Cloningers Temperament and Character Inventory) and levels of hopelessness (using Becks Hopelessness Scale), and studied the association between 5-HT(2a) receptor binding index, hopelessness and these personality dimensions. RESULTS When compared to normal controls, attempted suicide patients had a significantly lower binding potential of frontal 5-HT(2a) receptors, a higher level of hopelessness, a higher score on the temperament dimension harm avoidance and lower scores on the character dimensions self-directedness and cooperativeness. A significant correlation was found between harm avoidance, hopelessness and binding index in the population of patients that attempted suicide. LIMITATIONS The limited number of patients and potential ingestion of psychotropic drugs may influence the results of the study. CONCLUSIONS Lower central serotonergic function, hopelessness and harm avoidance are interrelated phenomena, which may increase the probability of the occurrence of attempted suicide.

Assessment of neuroinflammation and microglial activation in Alzheimer's disease with radiolabelled PK11195 and single photon emission computed tomography - A Pilot Study

Objectives: Inflammation contributes to degeneration in Alzheimer’s disease (AD), not simply as a secondary phenomenon, but primarily as a significant source of pathology. [123I]iodo-PK11195 is a single photon emission computed tomography (SPECT) ligand for the peripheral benzodiazepine receptor, the latter being expressed on microglia (brain resident macrophages) and upregulated under inflammatory circumstances. The objectives were to assess AD inflammation by detecting [123I]iodo-PK11195 uptake changes and investigate how uptake values relate with perfusion SPECT and neuropsychological findings. Methods: Ten AD and 9 control subjects were included. [123I]iodo-PK11195 SPECT images were realigned into stereotactic space where binding indices, normalized on cerebellar uptake, were calculated. Results: The mean [123I]iodo-PK11195 uptake was increased in AD patients compared with controls in nearly all neocortical regions; however, statistical significance was only reached in the frontal and right mesotemporal regions. Significant correlations were found between regional increased [123I]iodo-PK11195 uptake and cognitive deficits. Conclusions: [123I]iodo-PK11195 is a cellular disease activity marker and allows in vivo assessment of microglial inflammation in AD.

Early seizures in intracerebral hemorrhage Incidence, associated factors, and outcome

Objective: In patients with spontaneous intracerebral hemorrhage (ICH), the occurrence of early seizures (ES) may be a prognostic marker. Therefore, we aimed to identify incidence, associated factors, and influence on outcome of ES in patients with ICH. Methods: Between November 2004 and March 2009, we prospectively recruited 562 consecutive adults with a spontaneous ICH (Prognosis of InTra-Cerebral Hemorrhage cohort). Patients with previous seizures (n = 40) were excluded. ES were defined as seizures occurring within 7 days of stroke onset, and their associated factors were identified with Cox regression. For a subgroup of onset seizures, we used logistic regression. Data influencing outcome (mortality at day 7 and month 6 and functional outcome at month 6) were studied using survival analyses. Results: ES occurred in 71 (14%; 95% confidence interval [CI] 11–17) of 522 patients (274 male; median age 72 years, interquartile range 58–79 years). The only factor associated with ES was cortical involvement of ICH (odds ratio [OR] = 2.06; 95% CI 1.28–3.31). Regarding onset seizures (n = 38) (7%; 95% CI 5–10), associated factors were previous ICH (OR = 4.76; 95% CI 1.53–14.84), cortical involvement (OR = 2.21; 95% CI 1.11–4.43), younger age (OR = 0.97 per 1 year increase; 95% CI 0.95–0.99), and severity of the neurologic deficit at admission (OR = 1.03 per 1 point increase in the National Institutes of Health Stroke Scale score; 95% CI 1.01–1.06). ES did not influence vital or functional outcome. Conclusions: ES are a frequent complication in patients with spontaneous ICH; however, their occurrence does not influence outcome at 6 months.

Imaging of the 5-HT2A system: age-, gender-, and Alzheimer’s disease-related findings

Serotonin (5-HT) and more specifically the 5-HT(2A) receptor is involved in cognitive and non-cognitive behavior and plays an important role in Alzheimers disease (AD). The objective was to assess the 5-HT(2A) binding potential (BP) in healthy volunteers and AD with SPECT and 123I-5-I-R91150, a selective radio-iodinated 5-HT(2A) receptor antagonist. Twenty-six controls and nine AD patients were included. A semiquantitive analysis with normalization on cerebellar uptake provided estimates of BP for 26 cortical regions of interest. An age-related decline of neocortical BP was found (11.6% per decade). Compared to age-matched controls, a generally decreased neocortical BP in AD was found with a significant regional reduction in the orbitofrontal, prefrontal, lateral frontal, cingulate, sensorimotor, parietal inferior, and occipital region. These results are in line with previous postmortem, in vitro, and PET findings. The age-related decline highlights the necessity for matched advanced age study samples. The fact that the 5-HT(2A) receptor is differentially affected in AD patients has implications for both the etiological basis and therapeutic management of AD.

Is there a role for agonist gastrin-releasing peptide receptor radioligands in tumour imaging?

Gastrin-releasing peptide (GRP) has been shown to be a tumour growth stimulating agent for a number of normal and human cancer cell lines. The tumour growth effect is a direct result of GRP binding to membrane G-protein coupled GRP receptors (GRP-R) on the cell surface. Available data on the role of GRP and GRP-R in human lung, prostate, breast, colorectal and gastric carcinoma are reviewed and it is suggested that radiolabelled agonists are preferable to antagonists for imaging and therapy as they appear to be internalised, yielding a higher target/background ratio. The use of rhenium or indium radiolabels for therapy may provide a new approach to GRP/bombesin expressing tumours.

Biodistribution and displacement studies of the selective 5-HT2Areceptor antagonist 123I-5-I-R91150 in the normal dog

There is increasing interest in mapping receptors in vivo by using functional imaging modalities such as single photon emission tomography (SPET) and positron emission tomography (PET). Since SPET is a more accessible functional imaging modality than PET and, overall, it is more economical, radioligands suitable for this technique are in greater demand. Recently, 123I-5-I-R91150, a radioligand with high selectivity and affinity for 5-HT2A receptors in the brain, was introduced for SPET. This study reports on the whole-body distribution and brain uptake of the selective 123I-5-I-R91150 ligand in four normal dogs. The frontal to cerebellar ratio of uptake in time was determined in three dogs. Time-activity curve of venous blood was determined in one dog. Maximal global brain uptake was found at 10-60 min post-injection. Higher brain uptake was noted in the frontal cortical areas compared to the cerebellum. The frontal-cerebellar ratio reached the highest values at 90-180 min. Reversibility and pharmacological selectivity of ligand binding was demonstrated through displacement and blocking studies with the 5-HT2A receptor antagonist ketanserin. This study demonstrates that the specific 5-HT2A iodinated ligand can be used for imaging and semi-quantification of the 5-HT2A receptors in the canine brain in vivo by using SPET.

High-performance liquid chromatographic determination of [11C]1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide in mouse plasma and tissue and in human plasma

The high-performance liquid chromatographic determination of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide ([11C]PK 11195) is described. The method was successfully applied for plasma and tissue analysis after i.v. injection of [11C]PK 11195 in mice and for plasma analysis after administration of [11C]PK 11195 to humans. Separation is effected on a RP-C18 column, using a mixture of acetonitrile-water-triethylamine (65:35:0.5, v/v). Quantitative measurements of radioactivity are performed on a one-channel gamma-ray spectrometer equipped with a 2 x 2 in. NaI(Tl) detector. For humans rapid metabolisation of [11C]PK 11195 was observed. At 5, 20 and 35 min post injection 5%, 22% and 32%, respectively, of the plasma activity consisted of at least two more polar metabolites. Despite the extensive metabolisation rate in mice (up to 42% at 10 min post injection of [11C]PK 11195), no 11C-labelled metabolites could be detected in the extracts of brain and heart.

Synthesis and in vivo evaluation of [11C]zolpidem, an imidazopyridine with agonist properties at central benzodiazepine receptors

The synthesis and evaluation of [(11)C]zolpidem, an imidazopyridine with agonist properties at central benzodiazepine receptors, is reported herein. The reaction of desmethylzolpidem with [(11)C] methyl iodide afforded the title compound [(11)C]zolpidem in a yield of 19.19 +/- 3.23% in 41 +/- 2 min in specific activities of 0.995-1.19 Ci/micromol (1.115 +/- 0.105 Ci/micromol) (n = 3; decay corrected, EOB). The amount of radioactivity in the brain after tail vein injection in male Wistar rats was low, and the regional distribution was homogeneous and not consistent with the known distribution of the central benzodiazepine receptors. The frontal cortex/cerebellum ratio was not significantly greater than one (1.007 +/- 0.266 at 5 min) and did not increase from 5 to 40 min post-injection. A PET brain imaging study in one baboon confirmed the results obtained in rats. Therefore, it can be concluded that [(11)C]zolpidem is not a suitable tracer for in vivo visualization of central benzodiazepine receptors.

Biodistribution and dosimetry of (iodine-123)-iodomethyl-N,N-diethyltamoxifen, an (anti)oestrogen receptor radioligand.

Abstract. This study reports on the distribution and radiation dosimetry of iodine-123 labelled trans-Z-iodomethyl-N,N-diethyltamoxifen (123-ITX), a promising radioligand for prediction of the therapeutic efficacy of unlabelled tamoxifen in human breast carcinoma. Whole-body scans were performed up to 24 h after intravenous injection of 123-ITX (mean: 146 MBq, range: 142–148 MBq) in five female volunteers, four with and one without thyroid blockade. Blood samples were taken at various times up to 24 h after injection. Urine was also collected up to 24 h after injection, allowing calculation of renal clearance and interpretation of whole-body clearance. Time-activity curves were generated for the thyroid, heart, brain, breasts, liver and gallbladder by fitting the organ-specific geometric mean counts, obtained from regions of interest. The MIRD formulation was applied to calculate the absorbed radiation doses for various organs. The images showed rapid hepatobiliary excretion, resulting in good imaging conditions for the thoracic region, whereas imaging of the abdominal region was impeded by extensive bowel activity. The breast to non-specific uptake ratio increased over time. 123-ITX was cleared by both the kidneys and the gastrointestinal tract. At 50 h p.i. the mean excretion in the urine was 89.4% (SD 5.7%). If the thyroid was not blocked, it was one of the critical organs. The highest absorbed doses were received by the excretory organs, i.e. the urinary bladder wall, the lower and upper large intestine, and the gallbladder wall. The average effective dose of 123-ITX was estimated to be 0.0084 mSv/MBq. The amount of 123-ITX required for adequate imaging of tumoral uptake results in an acceptable effective dose to the patient.

Synthesis and in vivo evaluation of 7-chloro-5-[123I]iodo-4-oxo-1,4-dihydroquinoline-2-carboxylic acid.

As a possible radioligand for SPECT visualization of the NMDA receptors in the central nervous system, 7-chloro-5-[123I]iodokynurenic acid was prepared. This paper presents the synthesis of both the radioactive and the non-radioactive product, starting from 5-bromo-7-chlorokynurenic acid and using a non-isotopic nucleophilic halogen exchange reaction in the presence of iodide (Na123I or KI). Under the best labelling conditions, the radiochemical yield was 85%. The specific activity based on UV detection was found to be higher than 1 Ci/mumol (= 37 GBq/mumol) and the chemical and radiochemical (> 95%) purity of the tracer was checked by RP-HPLC.