Stig A. Larsson

Positron flight in human tissues and its influence on PET image spatial resolution

The influence of the positron distance of flight in various human tissues on the spatial resolution in positron emission tomography (PET) was assessed for positrons from carbon-11, nitrogen-13, oxygen-15, fluorine-18, gallium-68 and rubidium-82. The investigation was performed using the Monte Carlo code PENELOPE to simulate the transport of positrons within human compact bone, adipose, soft and lung tissue. The simulations yielded 3D distributions of annihilation origins that were projected on the image plane in order to assess their impact on PET spatial resolution. The distributions obtained were cusp-shaped with long tails rather than Gaussian shaped, thus making conventional full width at half maximum (FWHM) measures uncertain. The full width at 20% of the maximum amplitude (FW20M) of the annihilation distributions yielded more appropriate values for root mean square addition of spatial resolution loss components. Large differences in spatial resolution losses due to the positron flight in various human tissues were found for the selected radionuclides. The contribution to image blur was found to be up to three times larger in lung tissue than in soft tissue or fat and five times larger than in bone tissue. For 18F, the spatial resolution losses were 0.54xa0mm in soft tissue and 1.52xa0mm in lung tissue, compared with 4.10 and 10.5xa0mm, respectively, for 82Rb. With lung tissue as a possible exception, the image blur due to the positron flight in all human tissues has a minor impact as long as PET cameras with a spatial resolution of 5–7xa0mm are used in combination with 18F-labelled radiopharmaceuticals. However, when ultra-high spatial resolution PET cameras, with 3–4xa0mm spatial resolution, are applied, especially in combination with other radionuclides, the positron flight may enter as a limiting factor for the total PET spatial resolution—particularly in lung tissue.

Posture primarily affects lung tissue distribution with minor effect on blood flow and ventilation

We used quantitative single photon emission computed tomography to estimate the proportion of the observed redistribution of blood flow and ventilation that is due to lung tissue shift with a change in posture. Seven healthy volunteers were studied awake, breathing spontaneously. Regional blood flow and ventilation were marked using radiotracers that remain fixed in the lung after administration. The radiotracers were administered in prone or supine at separate occasions, at both occasions followed by imaging in both postures. Images showed greater blood flow and ventilation to regions dependent at the time of imaging, regardless of posture at radiotracer administration. The results suggest that a shift in lung parenchyma has a major influence on the imaged distributions. We conclude that a change from the supine to the prone posture primarily causes a change in the vertical distribution of lung tissue. The effect on the vertical distribution of blood flow and ventilation within the lung parenchyma is much less.

NCQ 298, a new selective iodinated salicylamide ligand for the labelling of dopamine D2 receptors.

NCQ 298 ((S)-3-iodo-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dimethoxysalicylamide) has an iodine substituent. We have labelled NCQ 298 with123I and125I, and used the radioligands as tracers in receptor studies in vitro, in vivo in autoradiography and in SPECT studies on Cynomolgus monkeys.[125I]NCQ 298 bound in vitro to a single binding site with a KD=19 pM. NCQ 298 has thus a 10-fold higher affinity for the dopamine D2 receptors than the corresponding des-5-methoxy compound FLA 961 (IBZM), previously used in SPECT studies. The binding of [125I]NCQ 298 was entirely reversible (T1/2=17.5 min at 37° C). Autoradiographical studies in vitro on rat and monkey brain tissue sections showed a distinct binding in caudate-putamen, nucleus accumbens, substantia nigra, and in layer 5 of the cerebral cortex. In vivo binding studies in mice showed a ratio of 10 between [125I]NCQ 298 binding in striatum and cerebellum. Binding was displaced by the selective dopamine D2 receptor antagonist raclopride. In SPECT studies with [123I]NCQ 298 in two Cynomolgus monkeys, radioactivity accumulated in the basal ganglia. The measured striatum to cerebellum ratio was about 15 after 3 h. A monkey brain phantom was constructed for the determination of conversion factors from pixel events to actual radioactivity. The resulting, corrected striatum to cerebellum ratio obtained was 30. After administration of 12 mg raclopride to one of the monkeys there was a substantial decrease in striatal radioactivity. [125I]NCQ 298 is a suitable ligand for the labelling of dopamine D2 receptors in vitro and in vivo. The specific properties of [123I]NCQ 298 suggest that this compound is a useful ligand for quantitative SPECT studies of dopamine D2 receptors in man.

Regional lung blood flow and ventilation in upright humans studied with quantitative SPECT

We used quantitative Single Photon Emission Computed Tomography (SPECT) to study the effect of the upright posture on regional lung blood flow and ventilation. Nine (upright) plus seven (prone and supine) healthy volunteers were studied awake, breathing spontaneously. Regional blood flow and ventilation were marked in sitting upright, supine and prone postures using (113m)In-labeled macroaggregates and inhaled Technegas ((99m)Tc); both remain fixed in the lung after administration. All images were obtained while supine. In comparison with horizontal postures, both blood flow and ventilation were greater in caudal regions when upright. The redistribution was greater for blood flow than for ventilation, resulting in decreasing ventilation-to-perfusion ratios down the lung when upright. We conclude that gravity redistributes regional blood flow and ventilation in the upright posture, while the influence is much less in the supine and prone postures.

Biodistribution and radiation dosimetry of the 18 kDa translocator protein (TSPO) radioligand [18F]FEDAA1106: a human whole-body PET study

Purpose[18F]FEDAA1106 is a recently developed positron emission tomography (PET) radioligand for in vivo quantification of the 18xa0kDa translocator protein [TSPO or, as earlier called, the peripheral benzodiazepine receptor (PBR)]. TSPO imaging is expected to be useful for the clinical evaluation of neuroinflammatory diseases. The aim of this study was to provide dosimetry estimates for [18F]FEDAA1106 based on human whole-body PET measurements.MethodsPET scans were performed for a total of 6.6xa0h after the injection of 183.8u2009±u20099.1xa0MBq of [18F]FEDAA1106 in six healthy subjects. Regions of interest were drawn on coronal images. Estimates of the absorbed doses of radiation were calculated using the OLINDA software.ResultsPeak uptake was largest in lungs, followed by liver, small intestine, kidney, spleen and other organs. Peak values of the percent injected dose (%ID) at a time after radioligand injection were calculated for the lungs (27.1%ID at 0.2xa0h), liver (21.1%ID at 0.6xa0h), small intestine (10.4%ID at 6.3xa0h), kidney (4.9%ID at 1.8xa0h) and spleen (4.6%ID at 0.6xa0h). The largest absorbed dose was found in the spleen (0.12xa0mSv/MBq), followed by kidneys (0.094xa0mSv/MBq). The calculated mean effective dose was 0.036xa0mSv/MBq.ConclusionBased on the distribution and dose estimates, the estimated radiation burden of [18F]FEDAA1106 is moderately higher than that of [18F]fluorodeoxyglucose (FDG). In clinical studies, the administered activity of this radioligand ought to be adjusted in line with regional regulations. This result would be helpful for further clinical TSPO imaging studies.

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.

The influence of photon depth of interaction and non-collinear spread of annihilation photons on PET image spatial resolution

PurposeThe quality of PET imaging is impaired by parallax errors. These errors produce misalignment between the projected location of the true origin of the annihilation event and the line of response determined by the coincidence detection system. Parallax errors are due to the varying depths of photon interaction (DOI) within the scintillator and the non-collinear (NC) emission of the annihilation photons. The aim of this work was to address the problems associated with the DOI and the NC spread of annihilation photons and to develop a quantitative model to assess their impact on image spatial resolution losses for various commonly used scintillators and PET geometries.MethodsA theoretical model based on Monte Carlo simulations was developed to assess the relative influence of DOI and the NC spread of annihilation photons on PET spatial resolution for various scintillator materials (BGO, LSO, LuAP, GSO, NaI) and PET geometries.ResultsThe results demonstrate good agreement between simulated, experimental and published overall spatial resolution for some commercial systems, with maximum differences around 1xa0mm in both 2D and 3D mode. The DOI introduces an impairment of non-stationary spatial resolution along the radial direction, which can be very severe at peripheral positions. As an example, the radial spatial resolution loss due to DOI increased from 1.3xa0mm at the centre to 6.7xa0mm at 20xa0cm from the centre of a BGO camera with a 412-mm radius in 2D mode. Including the NC, the corresponding losses were 3.0xa0mm at the centre and 7.3xa0mm 20xa0cm from the centre.ConclusionWithout a DOI detection technique, it seems difficult to improve PET spatial resolution and increase sensitivity by reducing the detector ring radius or by extending the detector in the axial direction. Much effort is expended on the design and configuration of smaller detector elements but more effort should be devoted to the DOI complexity.

Radioiodinated SB 207710 as a radioligand in vivo: imaging of brain 5-HT4 receptors with SPET

Single-photon emission tomography (SPET) and positron emission tomography (PET), when coupled to suitable radioligands, are uniquely powerful for investigating the status of neurotransmitter receptors in vivo. The serotonin subtype-4 (5-HT4) receptor has discrete and very similar distributions in rodent and primate brain. This receptor population may play a role in normal cognition and memory and is perhaps perturbed in some neuropsychiatric disorders. SB 207710 [(1-butyl-4-piperidinylmethyl)-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate] is a selective high-affinity antagonist at 5-HT4 receptors. We explored radioiodinated SB 207710 as a possible radioligand for imaging 5-HT4 receptors in vivo. Rats were injected intravenously with iodine-125 labelled SB 207710, euthanised at known times and dissected to establish radioactivity content in brain tissues. Radioactivity entered brain but cleared rapidly and to a high extent from blood and plasma. Between 45 and 75xa0min after injection, the ratios of radioactivity concentration in each of 12 selected brain tissues to that in receptor-poor cerebellum correlated with previous measures of 5-HT4 receptor density distribution in vitro. The highest ratio was about 3.4 in striatum. SB 207710 was labelled with iodine-123 by an iododestannylation procedure. A cynomolgus monkey was injected intravenously with [123I]SB 207710 and examined by SPET. Maximal whole brain uptake of radioactivity was 2.3% of the injected dose at 18xa0min after radioligand injection. Brain images acquired between 9 and 90xa0min showed high radioactivity uptake in 5-HT4 receptor-rich regions, such as striatum, and low uptake in receptor-poor cerebellum. At 169xa0min the ratio of radioactivity concentration in striatum to that in cerebellum was 4.0. In a second SPET experiment, the cynomolgus monkey was pretreated with a selective 5-HT4 receptor antagonist, SB 204070, at 20xa0min before [123I]SB 207710 injection. Radioactivity in all brain regions was reduced almost to the level in cerebellum by 176xa0min after radioligand injection. These findings show that [123I]SB 207710 is an effective radioligand for imaging brain 5-HT4 receptors in vivo.

Development of 123I-labelled NNC 13-8241 as a radioligand for SPECT visualization of benzodiazepine receptor binding☆

[125I]- and [123I]NNC 13-8241 were prepared from the trimethyltin precursor and radioactive iodide using the chloramine-T method. The total radiochemical yields of [125I]- and [123I]NNC 13-8241 were 60-70% and 40-50% respectively, with radiochemical purity higher than 98%. In binding studies with [125I]NNC 13-8241 in rats in vitro and in vivo a high uptake of radioactivity was demonstrated in brain regions known to have a high density of benzodiazepine (BZ) receptors such as the occipital and frontal cortex. SPECT examination with [123I]NNC 13-8241 in a Cynomolgus monkey demonstrated a high uptake of radioactivity in the occipital and frontal cortex. After displacement with flumazenil radioactivity in these brain regions was reduced to the level of a central region including the pons. Four hours after injection about 80% of the radioactivity in monkey plasma represented unchanged radioligand. This low degree of metabolism indicates that NNC 13-8241 is metabolically more stable than the radioligands hitherto developed for imaging of BZ-receptors in the primate brain.

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

Abstractu2002Rationale: 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.