Marleen Vandecapelle

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.

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.

In vivo evaluation of 4-[123I]iodo-N-{2-[4-(6-trifluoromethyl-2-pyridinyl)-1-piperazinyl]ethyl}benzamide, a potential SPECT radioligand for the 5-HT1A receptor

Abstract 4-[ 123 I]Iodo-N-{2-[4-(6-trifluoromethyl-2-pyridinyl)-1-piperazinyl]ethyl}benzamide (1. 123 I), a potential SPECT 5-HT 1A radioligand, was evaluated in vivo in rats. Biodistribution studies were performed leading to a % ID in the brain of 0.22 at 5 min p.i. No significant differences in % ID/g tissue of the different isolated brain regions (hippocampus, hypothalamus, striatum, cortex and cerebellum) could be demonstrated. Blocking experiments with 8-OH-DPAT, WAY100635 and ketanserin could not show any significant change in tracer uptake in the isolated brain regions. These data suggest that uptake in the brain does not represent binding of 1. 123 I to the 5-HT 1A receptor.

High performance liquid chromatographic determination of 123-I labeled tamoxifen metabolites in human plasma

A high-performance liquid chromatographic procedure for the quantitation of [(123)I]Iodomethyl-N,N-diethyltamoxifen (ITX), a radioligand for human breast cancer imaging, in human plasma is described. Separation was effected on a RP-C18 column, using a mixture of acetonitrile-water-triethylamine (70/30/0.5, v/v). ITX was rapidly cleared from human plasma and metabolites appeared as early as 7.5 min p.i. Quantitative assessment of metabolites in plasma over time allowed recalculation of the ITX plasma time-activity curve. Implications of ITX metabolite formation for breast tumour imaging are discussed.

Radioligands for Central Neuroreceptors

In the development of a new radioligand for a (sub)type of a central neuroreceptor, the selection of the ligand is of crucial importance. It should possess high affinity and selectivity for the concerned receptor type and be able to enter the brain without giving high nonspecific binding. Metabolism of the ligand is preferably slow or results in labelled metabolites that are unable to enter the brain. The incorporated radioisotope should have a physical half-life compatible with the imaging study done and its radiation should be of the correct type and energy to be detected by the external imaging system. Before entering the final developmental stage of in vivo evaluation in animals and human volunteers, a number of (radio)pharmaceutical quality control criteria should be drawn up for the new potential radioligand.