Andreas Wirrwar

4.5 tesla magnetic field reduces range of high-energy positrons-potential implications for positron emission tomography

We have theoretically and experimentally investigated the extent to which homogeneous magnetic fields up to 7 Tesla reduce the spatial distance positrons travel before annihilation (positron range). Computer simulations of a noncoincident detector design using a Monte Carlo algorithm calculated the positron range as a function of positron energy and magnetic field strength. The simulation predicted improvements in resolution, defined as full-width at half-maximum (FWBM) of the line-spread function (LSP) for a magnetic field strength up to 7 Tesla: negligible for F-18, from 3.35 mm to 2.73 mm for Ga-68 and from 3.66 mm to 2.68 mm for Rb-82. Also a substantial noise suppression was observed, described by the full-width at tenth-maximum (FWTM) for higher positron energies. The experimental approach confirmed an improvement in resolution for Ga-68 from 3.54 mm at 0 Tesla to 2.99 mm FWHM at 4.5 Tesla and practically no improvement for F-18 (2.97 mm at 0 Tesla and 2.95 mm at 4.5 Tesla). It is concluded that the simulation model is appropriate and that a homogeneous static magnetic field of 4.5 Tesla reduces the range of high-energy positrons to an extent that may improve spatial resolution in positron emission tomography.

Early detection of bony alterations in rheumatoid and erosive arthritis of finger joints with high-resolution single photon emission computed tomography, and differentiation between them

ObjectiveTo evaluate high-resolution multi-pinhole single photon emission computed tomography (MPH-SPECT) for the detection of bony alterations in early rheumatoid arthritis (ERA), early osteoarthritis (EOA) of the fingers and healthy controls.MethodsThe clinically dominant hands of 27 patients (13 ERA, nine EOA, five healthy controls) were examined by MPH-SPECT and bone scintigraphy. Additionally, magnetic resonance imaging (MRI) was performed in the ERA patients. Number of affected joints, localisation, pattern of tracer distribution and joint involvement were scored. Quantitative analysis was achieved by measurement of the region of interest (ROI) in all patients. The MPH-SPECT and MR images were fused in the ERA group.ResultsBone scintigraphy detected fewer joints (26 joints,13/22 patients) with increased tracer uptake than did MPH-SPECT (80 joints, 21/22 patients). Bone scintigraphy did not show recognisable uptake patterns in any group of patients. With MPH-SPECT central tracer distribution was typical in ERA (10/13 patients, EOA 2/9). In contrast, an eccentric pattern was found predominantly in EOA (7/9, ERA 2/13). Normalised counts were 4.5 in unaffected joints and up to 222.7 in affected joints. The mean uptake values in affected joints were moderately higher in the EOA patients (78.75, and 62.16 in ERA). The mean tracer uptake in affected joints was approximately three-times higher than in unaffected joints in both groups (ERA 3.64-times higher, EOA 3.58). Correlation with MR images revealed that bone marrow oedema and erosions matched pathological tracer accumulation of MPH-SPECT in 11/13. MPH-SPECT demonstrated increased activity in 2/13 patients with normal bone marrow signal intensity and synovitis seen on MR images.ConclusionMPH-SPECT is sensitive to early changes in ERA and EOA and permits them to be distinguished by their patterns of uptake.

High resolution SPECT in small animal research.

Single Photon Emission Computed Tomography (SPECT) is a technique used to assess physiological and biochemical processes under in vivo conditions. SPECT generates tomographic images from blood flow, glucose metabolism and receptor characteristics using radioactively labelled substances. This paper reviews the state of the art of in vivo imaging of laboratory animals in modified human and dedicated animal SPECT scanners. SPECT cameras with special collimators currently reach spatial resolutions up to 1 mm and sensitivities of about 1000 cps/MBq, allowing observation of receptor activity concentration changes in the pico-mole range. The time resolution of such cameras strongly depends on the pharmacological behaviour of the tracer and can range from several minutes to hours. Within these limits the functional characterization of many processes is possible. SPECT also offers the possibility to set up dynamic study protocols and repeated measurements of the same animal. This technique reduces the need for sacrificing animals, as was commonly practiced before the development of animal cameras. Animal SPECT gives the opportunity to monitor physiological and biochemical processes in animals in vivo, without interfering with the system under observation, and may become a valuable adjunct to the instrumentation (autoradiography, in vitro methods) of animal research.

Identification of task-specific rCBF changes in individual subjects: validation and application for PET.

Objective A method for identification and quantitative evaluation of task-specific changes of the regional cerebral blood flow (rCBF) measured with PET in activation studies of individual subjects is presented. The method is based on the statistical distributions of the quantitative and spatial information of regions of interest in rCBF subtraction images. Methods For validation, a cylindrical phantom of 20 cm diameter containing six spheres of 10–30 mm in diameter was used. The spheres representing the specific signals were filled with 18F, while one-tenth of this activity concentration was filled into the background compartment of the phantom representing “noise.” Of a sequence of dynamically recorded frames, subtraction images with different signal-to-noise ratios were calculated. Results In these subtraction images, our method allowed us to identify the larger spheres accurately and to quantify the signals. Comparison with t map analysis in averaged subtraction images revealed a high correspondence with the results obtained by our method in individual subtraction images. Based on this phantom validation, the method was applied for mapping of rCBF changes in humans. The rCBF was measured with [15O]butanol in four subjects during unilateral somatosensory discrimination and during rest. Conclusion The method proved to be capable of identifying task-specific rCBF changes in the contralateral motor, premotor, and sensory cortex accurately and with high quantitative and anatomical precision in each subject.

[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.

PurposeThis 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.MethodsSubsequent 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.ResultsStriatal 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.ConclusionThe 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.

Investigating the Dopaminergic Synapse In Vivo. II. Molecular Imaging Studies in Small Laboratory Animals

Dopaminergic synaptic function may be assessed either at the presynaptic terminal or at the postsynaptic binding sites using molecular in vivo imaging methods. Apart from the density of binding sites, parameters such as alterations in dopamine synthesis, dopamine storage or dopamine release can be quantified either by application of specific radiotracers or by assessing the competition between the exogenous radioligand and endogenous dopamine. The performance of animal studies allows the induction of specific short-term or long-term synaptic conditions via pharmacological challenges or infliction of neurotoxic lesions. Therefore, small laboratory animals such as rats and mice have become invaluable models for a variety of human disorders. This article gives an overview of those small animal studies which have been performed so far on dopaminergic neurotransmission using in vivo imaging methods, with a special focus on the relevance of findings within the functional entity of the dopaminergic synapse. Taken together, in vivo investigations on animal models of Parkinsons disease showed decreases of dopamine storage, dopamine release and dopamine transporter binding, no alterations of dopamine synthesis and DA release, and either increases or no alterations of D2 receptor binding, while in vivo investigations of animal models of Huntingtons disease. showed decreases of DAT and D1 receptor binding. For D2 receptor binding, both decreases and increases have been reported, dependent on the radioligand employed. Substances of abuse, such as alcohol, amphetamine and methylphenidate, led to an increase of dopamine release in striatal regions. This held for the acute application of substances to both healthy animals and animal models of drug abuse. Findings also showed that chronic application of cocaine induced long-term reductions of both D1 and D2 receptor binding, which disappeared after several weeks of withdrawal. Finally, preliminary results yielded the first evidence that acute pplication of haloperidol might induce a reduction of dopamine transporter binding, indicating an enhancement of dopamine release into the synaptic cleft. It is remarkable to what degree the findings obtained with small animal imaging devices correspond to the results of clinical and experimental studies on humans. This agreement underlines the validity of small animal imaging methods and demonstrates the feasibility of further investigations on animal models of human diseases.

Pretreatment with Haloperidol Reduces 123I-FP-CIT Binding to the Dopamine Transporter in the Rat Striatum: An In Vivo Imaging Study with a Dedicated Small-Animal SPECT Camera

Synaptic dopamine is mainly regulated by presynaptic dopamine transporter (DAT) activity. We hypothesized that variations in synaptic dopamine are reflected by variations of DAT radioligand binding. The effect of haloperidol, which increases synaptic dopamine concentrations, was therefore assessed in the rat striatum using 123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)-nortropane (123I-FP-CIT) as a DAT radioligand. Methods: Striatal 123I-FP-CIT binding was measured in 24 rats under baseline conditions (no pretreatment) and at 1 h after injection of haloperidol or a vehicle (1 mg/kg) using a small-animal SPECT camera. Results: Baseline equilibrium ratios (V3″) were 1.32 ± 0.24 (mean ± SD). After the haloperidol injection, V3″ decreased to 0.99 ± 0.38 (P2-tailed < 0.0001), corresponding to a mean reduction of DAT binding by 25%. Conclusion: Our results are indicative of competition between the DAT ligand 123I-FP-CIT and synaptic dopamine elevated by haloperidol, suggesting that the assessment of 123I-FP-CIT binding may be suitable to study variations in synaptic dopamine in vivo.

Development of a multi-pinhole detector for high-sensitivity SPECT imaging

We report on the development of a multi-pinhole detector for high-sensitivity SPECT imaging. The work is based on a high resolution SPECT system which already is in successful operation since a couple of months. The goal of the present work is to increase the sensitivity of the current detector by a factor of 30 to 40 and to optimize it for I-123 tracer development and evaluation. Besides improvements in the detector and aperture physics a multi-pinhole arrangement is envisaged. A series of Monte-Carlo simulations and preliminary phantom studies have shown the feasibility of this approach although a number of careful optimizations concerning the layout of the aperture geometry and the iterative reconstruction algorithm are still required. Results of the simulations and tests with simulated phantom data will be presented and the quality assessment procedures will be discussed.

Effects of l-DOPA on striatal iodine-123-FP-CIT binding and behavioral parameters in the rat

PurposeThe effect of clinical L-3,4-dihydroxyphenylalanine (L-DOPA) doses on the binding of [123I]N-&OHgr;-fluoropropyl-2&bgr;-carbomethoxy-3&bgr;-(4-iodophenyl)nortropane ([123I]FP-CIT) to the rat dopamine transporter (DAT) was investigated using small animal single-photon emission computed tomography. Materials and methodsDAT binding was measured at baseline, after challenge with the aromatic L-amino acid decarboxylase inhibitor benserazide, and after challenge with either 5 or 10 mg/kg L-DOPA plus benserazide. For baseline and challenges, striatal equilibrium ratios (V3′′) were computed as an estimation of the binding potential. Moreover, striatal V3′′ values were correlated with parameters of motor and exploratory behavior. ResultsV3′′ differed significantly between baseline and either dose of L-DOPA/benserazide. Moreover, V3′′ differed significantly between L-DOPA treatment groups. After 5 mg/kg L-DOPA/benserazide, DAT binding was inversely correlated with sitting duration (1–5 min) and sitting frequency (10–15 min). After 10 mg/kg L-DOPA/benserazide, an inverse correlation was found between DAT binding and sitting duration (1–30 min), whereas DAT binding and duration of ambulatory activity (1–30 min) as well as head and shoulder motility (10–15 min) exhibited a positive correlation. ConclusionChallenge with 5 and 10 mg/kg L-DOPA/benserazide led to mean reductions in DAT binding by 34 and 20%, respectively. Results indicate a biphasic response with a higher effect on DAT after the lower dose of L-DOPA. The reduction in DAT binding may be interpreted in terms of competition between [123I]FP-CIT and endogenous dopamine. Moreover, there is preliminary evidence of an association between striatal DAT and motor and exploratory parameters.

Pharmacological challenge and synaptic response - assessing dopaminergic function in the rat striatum with small animal single-photon emission computed tomography (SPECT) and positron emission tomography (PET).

Abstract Disturbances of dopaminergic neurotransmission may be caused by changes in concentrations of synaptic dopamine (DA) and/or availabilities of pre- and post-synaptic transporter and receptor binding sites. We present a series of experiments which focus on the regulatory mechanisms of the dopamin(DA)ergic synapse in the rat striatum. In these studies, DA transporter (DAT) and/or D2 receptor binding were assessed with either small animal single-photon emission computed tomography (SPECT) or positron emission tomography (PET) after pharmacological challenge with haloperidol, L-DOPA and methylphenidate, and after nigrostriatal 6-hydroxydopamine lesion. Investigations of DAT binding were performed with [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([123I]FP-CIT). D2 receptor bindingd was assessed with either [123I](S)-2-hydroxy-3-iodo-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide ([123I]IBZM) or [18F]1[3-(4′fluorobenzoyl)propyl]-4-(2-keto-3-methyl-1-benzimidazolinyl)piperidine ([18F]FMB). Findings demonstrate that in vivo investigations of transporter and/or receptor binding are feasible with small animal SPECT and PET. Therefore, tracers that are radiolabeled with isotopes of comparatively long half-lives such as 123I may be employed. Our approach to quantify DAT and/or D2 receptor binding at baseline and after pharmacological interventions inducing DAT blockade, D2 receptor blockade, and increases or decreases of endogenous DA concentrations holds promise for the in vivo assessment of synaptic function. This pertains to animal models of diseases associated with pre- or postsynaptic DAergic deficiencies such as Parkinson’s disease, Huntington’s disease, attention-deficit/hyperactivity disorder, schizophrenia or drug abuse.