Per-Olof Schnell

Mapping pathological (99m)Tc-d,l-hexamethylpropylene amine oxime uptake in Alzheimer's disease and frontal lobe dementia with SPECT.

Seventeen patients with probable Alzheimer’s disease (AD), 7 patients with frontal lobe dementia (FLD) and 19 control subjects (NOR) were examined by 99mTc-d,l- hexamethylpropylene amine oxime (99mTc-HMPAO) SPECT. Images were standardised in the same 3D space and averaged within each group. After normalisation, the three sets of images were analysed in all cerebral lobes, hippocampus, thalamus and basal ganglia. In AD, the 99mTc-HMPAO uptake values were significantly reduced, as compared to NOR, in the parietal, temporal and insular lobes. In patients with FLD, the uptake was altered in all lobes with the exception of the parietal lobe. The uptake in the nucleus caudatus decreased significantly in both AD and FLD as compared to NOR. The uptake in the anterior cingulate cortex was significantly reduced in FLD. Subtraction images highlighted all significantly decreased areas. In conclusion, standardising SPECT in a common space and subtracting data from a control group improves the visual interpretation of images. In this study, the typical temporo-parietal and fronto-parietal 99mTc-HMPAO uptake reductions were found in AD and FLD, respectively. The uptake in the nucleus caudatus was found to decrease significantly in AD and FLD and the one in the anterior cingulate cortex was reduced in FLD.

In vivo dynamical distribution of 131I-VIP in the rat studied by gamma-camera

The in vivo distribution of vasoactive intestinal peptide (VIP) was studied for the first time using a rat model in combination with labeled VIP (131I-VIP) and a gamma-camera. A dynamic scan showed that 131I-VIP was cleared rapidly from the blood circulation. The radioactivity was taken up and accumulated in the lungs during the first minute. During the next 15 min, the radioactivity was slowly removed from the lungs and redistributed into the kidneys, gastric mucosa, liver and small intestine. However, the radioactivity extracted by the lungs was about 6-fold lower during the first minute when a large amount of the non iodinated VIP was coinjected with the 131I-VIP. 131I-VIP was eliminated rapidly from the blood with a half-life of 0.44 +/- 0.05 (min +/- SD) while in lung the elimination half-life was determined to 2.3 +/- 0.8 (min +/- SD). Of the radioactivity in the lungs, 2% was found to be intact 131I-VIP after 20 min. In all other organs the radioactivity found was assumed to be low molecular weight fragments of 131I-VIP. We suggest that lungs play an important role to extract VIP from the circulation after an i.v. administration. 131I-VIP degradation products are redistributed mostly to the kidneys and to the gastric mucosa to be excreted through urine and stomach contents, respectively.

Iodine-123 labelled Z-(R,R)-IQNP: a potential radioligand for visualization of M1 and M2 muscarinic acetylcholine receptors in Alzheimer’s disease

Abstract.Z-(R)-1-Azabicyclo[2.2.2]oct-3-yl (R)-α-hydroxy-α-(1-iodo-1-propen-3-yl)-α-phenylacetate (Z-IQNP) has high affinity to the M1 and M2 muscarinic acetylcholine receptor (mAChR) subtypes according to previous in vitro and in vivo studies in rats. In the present study iodine-123 labelled Z-IQNP was prepared for in vivo single-photon emission tomography (SPET) studies in cynomolgus monkeys. SPET studies with Z-[123I]IQNP demonstrated high accumulation in monkey brain (>5% of injected dose at 70 min p.i.) and marked accumulation in brain regions such as the thalamus, the neocortex, the striatum and the cerebellum. Pretreatment with the non-selective mAChR antagonist scopolamine (0.2 mg/kg) inhibited Z-[123I]IQNP binding in all these regions. The percentage of unchanged Z-[123I]IQNP measured in plasma was less than 10% at 10 min after injection, which may be due to rapid hydrolysis, as has been demonstrated previously with the E-isomer of IQNP. Z-[123I]IQNP showed higher uptake in M2-rich regions, compared with previously obtained results with E-[123I]IQNP. In conclusion, the radioactivity distribution from Z-[123I]IQNP in monkey brain indicates that Z-[123I]IQNP binds to the M1- and M2-rich areas and provides a high signal for specific binding, and is thus a potential ligand for mAChR imaging with SPET.

A comparison of the imaging properties of a 3- and 4-ring biograph PET scanner using a novel extended NEMA phantom

The imaging quality of a Siemens biograph PET/CT camera was evaluated before and after an axial field of view (FOV) upgrade from 16.2 cm (TruePoint, 3-rings) to 21.6 cm (TrueV, 4-rings). A series of five measurements were performed with the original 3- and with the upgraded 4-ring system using the original, as well as a newly developed modified IEC/2001-NEMA phantom with thoracic and abdominal lucite extensions. A scan protocol comprising five different measurements was used; 1) the pure IEC phantom positioned at the center of FOV 2) IEC, positioned 100 mm off-axis, 3) IEC, with thoracic slabs, positioned at the center, 4) IEC, with abdominal slabs, positioned at the center, 5) the same as in 1) but with approximately half the 18F-activity. All measurements were performed and reconstructed according to the standard whole-body PET/CT protocol. For hot spheres, the average contrast was improved (between 8 and 23%) for all spheres of scan 1 and 2 with the upgraded system. With extension slabs, the hot sphere contrast gave no clear-cut results. The contrast impaired for the smallest spheres but increased for the two largest spheres with the upgraded system. For cold spheres, no contrast improvement was observed in any of the scans with the upgraded camera. Instead there was up to 14% reduction in cold sphere contrast in the phantom measurements with extension slabs. The reduced cold sphere contrast in the phantom with extension slabs may be due to difficulties in correcting for the increased scatter fraction.

Z-IQNP : a potential radioligand for SPECT imaging of muscarinic acetylcholine receptors in Alzheimer's disease

Abstract Rationale: The density of the M2 subtype of muscarinic acetylcholine receptors (mAChR) has been shown to be reduced in the brain of patients with Alzheimer’s disease (AD). It is therefore of interest to develop a brain imaging method for diagnostic purposes. Z-(R,R)-1-azabicyclo[2.2.2]oct-3-yl α-hydroxy-α-(1-iodo-1-propen-3-yl)-α-phenylacetate (Z-IQNP) is a muscarinic antagonist with high affinity for the M2 subtype. Objective: The pharmacological characteristics and topographic distribution of radiolabelled Z-IQNP as a radioligand for the M2 mAChR subtype were examined in vitro and in vivo. Methods: Z-IQNP was labelled with 125I and 123I. Autoradiography was performed on whole-hemisphere cryosections from human post mortem brains. SPECT was performed in a cynomolgus monkey. Results: Autoradiography showed binding of [125I]Z-IQNP in all brain regions, which was inhibited by the non-selective muscarinic antagonist scopolamine. The addition of BIBN 99, a compound with high affinity for the M2 subtype, inhibited [125I]Z-IQNP binding particularly in the cerebellum, which has a high density of the M2 subtype. SPECT demonstrated high uptake of [123I]Z-IQNP in all brain regions. The binding was markedly reduced in all brain regions after pretreatment with the non-selective muscarinic antagonist dexetimide and also the M1 antagonist biperiden. Dexetimide markedly inhibited [123I]Z-IQNP binding in the cerebellum, which is consistent with a high density of M2-receptors in this region. The sigma receptor binding compound DuP 734 had no effect on Z-IQNP binding either in vitro or in vivo. Conclusions: This study indicates that radiolabelled Z-IQNP has high specificity for mAChR with higher affinity for the M2 than the M1 subtype and negligible affinity for sigma recognition sites both in vitro and in vivo. [123I]Z-IQNP should be useful for future SPECT studies in AD for examination of the density of M2 receptors particularly in the cerebellum.

Blood Pool Scintigraphy of the Skull in Relation to Head‐Down Tilt Provocation in Patients With Chronic Tension‐Type Headache and Controls

Objective.—To investigate the mechanisms behind the increase of chronic tension‐type headache during head‐down tilt.

Effect of size fractionation on the distribution of an albumin colloid in the reticuloendothelial system of the mouse

To study if by varying the particle size of a 99mTc albumin colloid preparation its relative bone marrow accumulation could be increased, it was separated by gel filtration and different fractions were injected into mice. Particles around and smaller than the peak size of the colloid, 31 nm, exhibited a higher bone marrow/liver-spleen uptake ratio than larger particles but the uptake ratio was similar to that of the unseparated colloid. An antimony sulphide colloid showed a similar particle size distribution, but the corresponding uptake ratio was half of the albumin colloid. This indicates that characteristics other than size determine the distribution of a colloid in the reticuloendothelial system.

Evaluation and Metabolite Studies of 125I- and 123I-Labelled E-(R,R)-IQNP: Potential Radioligands for Visualization of M1 Muscarinic Acetylcholine Receptors in Brain

A new ligand for the M1 muscarinic receptor subtype, E-(R,R)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (E-IQNP), was labelled with 125I and 123I for autoradiographic studies on human whole-brain cryosections and SPET studies, respectively, in Cynomolgus monkey. Autoradiography demonstrated E-[125I]IQNP binding in M1 receptor-rich regions such as the neocortex and the striatum. The binding was displaceable by the selective M1 antagonist biperiden. In vivo single photon emission tomography (SPET) studies with E-[123I]IQNP demonstrated a high accumulation of radioactivity in the monkey neocortex. Rapid hydrolysis of the quinuclidinyl ester to the free acid was found to be a major biotransformation route for E-[123I]IQNP. The free acid of E-[123I]IQNP does not pass the blood-brain barrier, but the plasma concentration was high as compared to the total radioactivity in brain. It is thus necessary to correct for the high concentration of radioactive metabolites in parenchymal blood (CBV) to obtain accurate values for E-[123I]IQNP binding in brain.

Can pharmacological intervention improve the visualization of the reticuloendothelial system using 99mTc-labeled albumin nanocolloid to that achievable with 111In-labeled granulocytes? experimental studies in mice

The use of 99mTc-colloids for bone marrow scintigraphy is limited by a high liver uptake, which hampers the evaluation of surrounding skeletal structures. In an experimental mouse system, different measures to increase the bone marrow activity in relation to the liver activity have been tested. A slightly positive, but significant, outcome was achieved by three different measures, namely fasting, pretreatment with a calcium-blocking pharmaceutical (Nimodipine) and pretreatment with large amounts of a gelatine colloid. It is concluded that the possibilities of dramatically improving the bone marrow uptake of a colloid compared to the liver are limited and not comparable to that achievable using radiolabeled granulocytes.