Dynamic observation of the three-dimensional distribution of labeled liposomes using the novel high-resolution single-photon emission computed tomography.

The aim of this study was to show that the multipinhole technique (high-resolution single-photon emission computed tomography [HiSPECT]) is suitable for dynamic imaging of both biodistribution and temporal uptake behavior of radiolabeled cationic liposomes in Balb/c-mice. HiSPECT uses multipinhole collimators adapted to a clinical SPECT scanner, together with a dedicated iterative reconstruction program. This technique provides both high spatial resolution and an improvement in sensitivity. Six male Balb/c mice received 9.8 +/- 4.0 MBq of the In 111-labeled liposomes. The measurements started directly after the injection and tomographic data were acquired in steps of 5 minutes. The regional evaluation displayed a high initial uptake of liposomes in the lungs (45.4%), which decreased to 25.1% after 30 minutes and to below 2% after 48 hours. In contrast, liver uptake increased in the first 30 minutes from 13.1 to 21.2% and remained relatively stable at 24.4% (24 hours) and 18.8% (48 hours). The data are interpreted as a slow shift of liposomes from the lungs into the liver and later to other organs such as the spleen and bladder. This study shows that the HiSPECT technique is capable of dynamically visualizing the uptake behavior of radioactively labeled liposomes in vivo with high temporal and spatial resolution.

Challenge by the murine brain: multi-pinhole SPECT of 123I-labelled pharmaceuticals.

This protocol presents an improved method for SPECT imaging based on multi-pinhole techniques, applied to the visualisation of neurotracers in small animal models. Three types of collimators with 6-pinhole apertures adapted to special requirements for the imaging of the brain of mice and rats and to full body imaging in mice are employed in the experiments. A conventional triple-headed TRIAD/Trionix SPECT system was upgraded with pyramidal supports and shieldings onto the multi-pinhole collimators were installed. The system was employed for the assessment of the uptake of [123I]FP-CIT and [123I]IBZM, well known tracers of dopamine transport and dopamine D2/D3 receptors, respectively. Requirements regarding the applied radioactivity are reported, as well as further conditions determining the effectiveness of the detection of the uptake of [123I]FP-CIT and [123I]IBZM. The measurements in mice required only 20-25% of the activity described in previous studies. Dynamic measurements are presented, with a time resolution as high as 10 min in the brain of rats. Due to the lower signal intensity obtained for mice, the time resolution was 42min for [123I]FP-CIT, with a ratio ROI/background of 5.4, and 17 min for [123I]IBZM, with the ratio ROI/background of 4.5 (1.6-7.4).

Efficacy of 99mTc pertechnetate and 131I radioisotope therapy in sodium/iodide symporter (NIS)-expressing neuroendocrine tumors in vivo.

PURPOSE: There is growing interest in the human sodium/iodide symporter (NIS) gene both as a molecular imaging reporter gene and as a therapeutic gene. Here, we show the feasibility of radioisotope therapy of neuroendocrine tumors. As a separate application of NIS gene transfer, we image NIS-expressing tumors with pinhole SPECT in living subjects. METHODS: Biodistribution studies and in vivo therapy experiments were performed in nude mice carrying stably NIS-expressing neuroendocrine tumor xenografts following i.v. injection of (131)I and (99m)Tc pertechnetate. To show the usefulness of NIS as an imaging reporter gene, (99m)Tc pertechnetate uptake was imaged in vivo using a clinical gamma camera in combination with a custom-made single pinhole collimator, followed by SPECT/small animal MRI data coregistration. RESULTS: NIS-expressing neuroendocrine tumors strongly accumulated (131)I and (99m)Tc pertechnetate, as did thyroid, stomach, and salivary gland. The volume of NIS-expressing neuroendocrine tumors decreased significantly after therapeutic administration of (131)I or (99m)Tc pertechnetate, whereas control tumors continued to grow. NIS-mediated uptake of (99m)Tc pertechnetate could be imaged in vivo at high resolution with a clinical gamma camera equipped with a custom-made single pinhole collimator. High-resolution functional and morphologic information could be combined in a single three-dimensional data set by coregistration of SPECT and small animal MRI data. Lastly, we demonstrated a therapeutic effect of (99m)Tc pertechnetate on NIS-expressing neuroendocrine tumors in cell culture and, for the first time, in vivo, thought to be due to emitted Auger and conversion electrons. CONCLUSIONS: NIS-expressing neuroendocrine tumors efficiently concentrate radioisotopes, allowing for in vivo high-resolution small animal SPECT imaging as well as rendering possible successful radioisotope therapy of neuroendocrine tumors.

[123I]Iodobenzamide binding to the rat dopamine D2 receptor in competition with haloperidol and endogenous dopamine--an in vivo imaging study with a dedicated small animal SPECT.

PURPOSE: This study assessed [123I]iodobenzamide binding to the rat dopamine D2 receptor in competition with haloperidol and endogenous dopamine using a high-resolution small animal SPECT. METHODS: Subsequent to baseline quantifications of D2 receptor binding, imaging studies were performed on the same animals after pre-treatment with haloperidol and methylphenidate, which block D2 receptors and dopamine transporters, respectively. RESULTS: Striatal baseline equilibrium ratios (V3'') of [123I]iodobenzamide binding were 1.42+/-0.31 (mean+/-SD). After pre-treatment with haloperidol and methylphenidate, V3'' values decreased to 0.54+/-0.46 (p<0.0001) and 0.98+/-0.48 (p=0.009), respectively. CONCLUSION: The decrease in [123I]iodobenzamide binding induced by pre-treatment with haloperidol reflects D2 receptor blockade, whereas the decrease in receptor binding induced by pre-treatment with methylphenidate can be interpreted in terms of competition between [123I]IBZM and endogenous dopamine. Findings show that multiple in vivo measurements of [123I]iodobenzamide binding to D2 receptors in competition with exogenous and endogenous ligands are feasible in the same animal. This may be of future relevance for the in vivo evaluation of novel radioligands as well as for studying the interrelations between pre- and/or postsynaptic radioligand binding and different levels of endogenous dopamine.

[TierSPECT: performance of a dedicated small-animal-SPECT camera and first in vivo measurements]. / TierSPECT: Leistungsparameter einer dedizierten Kleintier-SPECT-Kamera und erste in vivo Messungen.

This paper presents the performance of a new small-animal camera (TierSPECT) devised for the in vivo measurements of radiolabeled substances in small laboratory animals such as mice and rats. In a scatter medium, the camera has a tomographic spatial resolution of 2.87 mm and a sensitivity of 22 cps/MBq in a usable Field-of-View (FOV) with a diameter of 82 mm. The planar homogeneity amounts to 3.3%, the tomographic homogeneity lies between 3.2% and 3.5%. The deviation between filled and measured concentration of activity in a cylindrical 4-chamber-phantom was smaller than 2.6%. Using a novel rat head phantom with chamber volumes in the order of magnitude of the spatial resolution (between 0.065 ml and 0.19 ml) it could be demonstrated that studies of the rat neostriatal dopaminergic system are feasible under observance of physiological conditions. In vivo studies using [99mTc]diphosphonato-1,2-propandicarbonic acid (99mTc-DPD) and [123I]N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)-nortropane (123I-FP-CIT) proved that bone metabolism and dopamine transporter binding can be visualized with the TierSPECT. The fusion of 99mTc-DPD and 123I-FP-CIT images allowed the differentiation between intra- and extracerebral structures. Pretreatment with methylphenidate resulted in blockade of striatal dopamine transporter binding.

Quantitation of dopamine transporter blockade by methylphenidate: first in vivo investigation using [123I]FP-CIT and a dedicated small animal SPECT.

PURPOSE: The aim of this study was to investigate the feasibility of assessing dopamine transporter binding after treatment with methylphenidate in the rat using a recently developed high-resolution small animal single-photon emission computed tomograph (TierSPECT) and [123I]FP-CIT. METHODS: [123I]FP-CIT was administered intravenously 1 h after intraperitoneal injection of methylphenidate (10 mg/kg) or vehicle. Animals underwent scanning 2 h after radioligand administration. The striatum was identified by superimposition of [123I]FP-CIT scans with bone metabolism and perfusion scans obtained with 99mTc-DPD and 99mTc-tetrofosmin, respectively. As these tracers do not pass the blood-brain barrier, their distribution permits the identification of extracerebral anatomical landmarks such as the orbitae and the harderian glands. The cerebellum was identified by superimposing [123I]FP-CIT scans with images of brain perfusion obtained with 99mTc-HMPAO. RESULTS: Methylphenidate-treated animals and vehicle-treated animals yielded striatal equilibrium ratios (V''3) of 0.24+/-0.26 (mean +/- SD) and 1.09+/-0.42, respectively (t test, two-tailed, p<0.0001). Cortical V''3 values amounted to 0.05+/-0.28 (methylphenidate) and 0.3+/-0.39 (saline, p=0.176). This first in vivo study of rat dopamine transporter binding after pre-treatment with methylphenidate showed a mean reduction of 78% in striatal [123I]FP-CIT accumulation. CONCLUSION: The results can be interpreted in terms of a pharmacological blockade in the rat striatum and show that in vivo quantitation of dopamine transporter binding is feasible with [123I]FP-CIT and the TierSPECT. This may be of future relevance for in vivo investigations on rat models of attention deficit/hyperactivity disorder. Furthermore, our findings suggest that investigations in other animal models, e.g. of Parkinson's and Huntington's disease, may be feasible using SPECT radioligands and small animal imaging systems.