Effects of the method of drawing regions of interest on the differential diagnosis of extrapyramidal syndromes using 123I-iodolisuride SPET.

Various parameters are currently used for the semi-quantitative assessment of dopamine D2 receptors and differ according to the delineation of the striatal region of interest (ROI) and the choice of the reference ROI. The aim of this study was to assess the value of different ROI approaches in differentiating patients with normal or increased numbers of D2 dopamine receptors (group 1 = Parkinson's disease, n = 8) from patients with decreased dopamine D2 receptors (group 2 = other extrapyramidal syndromes, n = 9) using 123I-iodolisuride SPET (ILIS-SPET). 123I-iodolisuride (190 +/- 31 MBq) and 99Tcm-ethyl cysteinate dimer (99Tcm-ECD) perfusion SPET were performed in the same position, with a dual-headed gamera camera equipped with fan beam collimators. Both a geometric approach (ellipse, circle or rectangle) and an anatomical approach using the CT scan and perfusion SPET as anatomical guides were used to draw striatal and reference ROIs. A total of 33 different parameters were calculated for each patient, indicating the ratio of counts between the striatal and reference ROIs (frontal, occipital cortex or cerebellum) and the asymmetry between the right and left striatum. More significant differences between group 1 and group 2 were found by using geometric ROIs than by using anatomical ROIs. The most discriminant ratios were the caudate/occipital, caudate/frontal and striatum/occipital ratios (P = 0.001, P = 0.002, P = 0.003 respectively). A close correlation was found between the striatum/caudate and striatum/occipital ratios, but not between the striatum/frontal and striatum/occipital ratios or between the striatum/frontal and striatum/caudate ratios. We conclude that the occipital cortex is the best reference for the semi-quantitative evaluation of dopamine D2 receptors as the frontal cortex could include some dopamine D2 receptor-bound radioligand, and that the caudate/occipital ratio is an appropriate parameter for differentiating Parkinson's disease from non-Parkinson extrapyramidal syndrome by 123I-iodolisuride SPET.

A selective radiobrominated cocaine analogue for imaging of dopamine uptake sites: pharmacological evaluation and PET experiments.

(E)-N-(3-bromoprop-2-enyl)-2beta-carbomethoxy-3beta-4'-tolyl -nortropane or PE2Br, an analogue of cocaine was labelled with the positron emitter 76Br (T1/2=16 h) for pharmacological evaluation in the rat and PET investigation in the monkey. [76Br]PE2Br was obtained by electrophilic substitution from the tributylstannyl precursor with radiochemical yield of 80%. In vivo biodistribution studies of [76Br]PE2Br (20 MBq/nmol) in rats showed a high uptake in the striatum (2.2% ID/g tissue at 15 min p.i.). The striatum to cerebellum radioactivity ratio was 6 at 1 hour p.i. Striatal uptake of [76Br]PE2Br was almost completely prevented by pretreatment with GBR 12909, but citalopram and maprotiline had no effect, confirming the selectivity of the radioligand for the dopamine transporter. PET imaging of the biodistribution of [76Br]PE2Br in the baboon demonstrated rapid and high uptake in the brain (5% ID at 3 min p.i.). The striatal radioactivity concentration reached a plateau at 20 min p.i. (7% ID/100 mL). The uptake in the cortex and cerebellum was very low. A significantly higher uptake in the thalamus was observed. At 1h p.i., the striatum to cerebellum ratio and thalamus to cerebellum ratio were 8 and 1.9 respectively. In competition experiments the radioactivity in the striatum and the thalamus was displaced by 5 mg/kgof cocaine and 5 mg/kg of GBR 12909, but citalopram and maprotiline had no effect. These results showed that [76Br]PE2Br is in vivo a potent and selective radioligand suitable for PET imagingof the dopamine transporter.

Dietary fish oil affects monoaminergic neurotransmission and behavior in rats.

We studied the effects of a fish oil enriched diet on fatty acid composition of cerebral membranes and on several neurochemical and behavioral variables of monoaminergic function in rats. The frontal cortex, striatum, hippocampus and cerebellum were studied in rats fed fish oil (FPO, 50% salmon oil + 50% palm oil), which provided an (n-6)/(n-3) polyunsaturated fatty acid (PUFA) ratio of 0.14 versus 6. 19 in controls fed a diet containing a mixture of African peanut oil and rapeseed oil. In the FPO group compared to the control group, the major modifications in fatty acid composition of cerebral membranes included the following: higher levels in 22:6(n-3), lower levels in 20:4(n-6) and a significantly greater proportion of phosphatidylserine. Dopamine levels were 40% greater in the frontal cortex of rats fed FPO than from those fed the control diet. In this cerebral region there was also a reduction in monoamine oxidase B (MAO-B) activity and greater binding to dopamine D2 receptors. By contrast, a lower binding to dopamine D2 receptors (-7%) was observed in the striatum. Ambulatory activity was also reduced in FPO-fed rats, possibly related to observed changes in striatal dopaminergic receptors. This suggested that the level of (n-6) PUFA, which was considerably lower in the FPO diet than in the control diet, could act on locomotion through an effect on striatal dopaminergic function, whereas the high level of (n-3) PUFA could act on cortical dopaminergic function.

Chronic n-3 polyunsaturated fatty acid diet-deficiency acts on dopamine metabolism in the rat frontal cortex: a microdialysis study.

The effects of alpha-linolenic acid diet deficiency on rat dopaminergic metabolism were investigated in the frontal cortex of male 2-3 month-old rats using the microdialysis method. Increased basal levels of dopamine metabolites were observed in the frontal cortex of awake deficient rats, without modification of dopamine levels. Moreover, using KCl perfusion which releases newly synthesized dopamine, no difference was observed in anaesthetized deficient rats versus control rats. In addition, a decrease in dopamine release was observed in anaesthetized deficient rats versus control rats after tyramine stimulation, which is known to induce release of dopamine from vesicular stores. A working model is proposed which suggests that a chronic n-3 polyunsaturated fatty acids (PUFA) deficiency may lead to modifications in the internalization of dopamine in the storage pool in the frontal cortex.

alpha-Linolenic acid dietary deficiency alters age-related changes of dopaminergic and serotoninergic neurotransmission in the rat frontal cortex.

The effects of alpha-linolenic acid diet deficiency on rat dopaminergic and serotoninergic neurotransmission systems were investigated in the frontal cortex, striatum, and cerebellum of male rats 2,6,12, and 24 months of age. The diet deficiency induced severe decrease in the 22:6n-3 fatty acid levels in all regions and a compensatory increase in n-6 fatty acid levels. A recovery in the levels of 22:6n-3 was observed in deficient rats between 2 and 12 months of age; however, this recovery was lower in frontal cortex than in striatum and cerebellum. In the striatum and cerebellum, dopaminergic and serotoninergic receptor densities and endogenous dopamine and serotonin levels were affected by aging regardless of the diet. In contrast, a 40-75% lower level of endogenous dopamine in the frontal cortex occurred in deficient rats according to age. The deficiency also induced an 18-46% increase in serotonin 5-HT2 receptor density in the frontal cortex during aging, without variation in endogenous serotonin level, and a 10% reduction in density of dopaminergic D2 receptors. Monoamine oxidase-A and -B activities showed specific age-related variations but regardless of the diet. Our results suggest that a chronically alpha-linolenic-deficient diet specifically affects the monoaminergic systems in the frontal cortex.

Iododerivative of pargyline: a potential tracer for the exploration of monoamine oxidase sites by SPECT.

Monoamine oxidases are important in the regulation of monoaminergic neurotransmission. An increase in monoamine oxidase B (MAO B) has been observed in some neurodegenerative diseases, and therefore quantification of cerebral MAO B activity by SPECT would be useful for the diagnosis and therapeutic follow-up of these disorders. We have developed an iodinated derivative of pargyline, a selective inhibitor of MAO B, in order to explore this enzyme by SPECT. Stable bromo and iodo derivatives of pargyline were synthesized and chemically characterized. The radioiodinated ligand [125I]-2-iodopargyline was obtained with high specific activity from the bromo precursor by nucleophilic exchange. Affinity and selectivity of 2-iodopargyline were tested in vitro. Biodistribution study of [125I]-2-iodopargyline was performed in rats. Radioiodinated ligand were obtained in a no-carrier-added form. 2-iodopargyline has a higher in vitro affinity for MAO B than pargyline. However, the in vitro selectivity for MAO B was better for pargyline than for 2-iodopargyline. Ex vivo autoradiographic studies and in vivo saturation studies with selective inhibitors of MAO showed that the cerebral biodistribution of [125I]-2-iodopargyline in the rat is consistent with high level binding to MAO B sites in the pineal gland and in the thalamus. In conclusion, 2-iodopargyline preferentially binds in vivo to MAO B sites with high affinity. However, its selectivity for MAO B in rats is not very high, whereas this ligand binds to a lesser extent to MAO A. It will be then of great value to evaluate the specificity of 2-iodopargyline in humans. This new ligand labeled with 123I should therefore be a suitable tool for SPECT exploration of MAO B in the human brain.

[125I]MIBG uptake and release in different regions of the rat brain.

Radioiodinated m-iodobenzylguanidine [( 125I]MIBG) and tritiated norepinephrine [( 3H]NE]) uptake and release were compared, in different regions of the brain of the rat. The classification of the regions according to uptake was the same for both tracers:striatum greater than hypothalamus greater than hippocampus greater than cortex greater than brainstem. Tetrabenazine (TBZ), a granular monoamine uptake inhibitor reduced the uptake in the different regions. The inhibition rate was higher for [3H]NE uptake than for [125I]MIBG. The spontaneous release was the same for [125I]MIBG and [3H]NE and was the lowest in the striatum. The K+ stimulated release of [3H]NE was more complete than the release of [125I]MIBG and was the most important in the striatum. From these results, it is inferred that MIBG enters the brain tissue via NE uptake mechanisms. It appears that MIBG is stored in the chromaffin granules, as NE, but also in the cytoplasm. A modified molecule derived from MIBG which would cross the blood-brain barrier, would then appear as a potential scintigraphic marker of monoamine uptake, storage and release.