Browsing by Author "Meikle, SR"
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- ItemThe 18 kDa translocator protein (peripheral benzodiazepine receptor) expression in the bone of normal, osteoprotegerin or low calcium diet treated mice(PLOS ONE, 2012-01-25) Kam, WWY; Meikle, SR; Dunstan, CR; Banati, RB; Blair, JM; Zheng, YThe presence of the translocator protein (TSPO), previously named as the mitochondrial or peripheral benzodiazepine receptor, in bone cells was studied in vitro and in situ using RT-qPCR, and receptor autoradiography using the selective TSPO ligand PK11195. In vitro, the TSPO is highly expressed in osteoblastic and osteoclastic cells. In situ, constitutive expression of TSPO is found in bone marrow and trabecular bone, e.g., spongiosa. Mice with a reduction of bone turnover induced by a 4-day treatment of osteoprotegerin reduces [3H]PK11195 binding in the spongiosa (320±128 Bq.mg−1, 499±106 Bq.mg−1 in saline-treated controls). In contrast, mice with an increase in bone turnover caused by a 4-day low calcium diet increases [3H]PK11195 binding in the spongiosa (615±90 Bq.mg−1). Further, our study includes technical feasibility data on [18F]fluoride microPET imaging of rodent bone with altered turnover. Despite [18F]fluoride having high uptake, the in vivo signal differences were small. Using a phantom model, we describe the spillover effect and partial volume loss that affect the quantitative microPET imaging of the small bone structures in experimental mouse models. In summary, we demonstrate the expression of TSPO in small rodent bone tissues, including osteoblasts and osteoclasts. A trend increase in TSPO expression was observed in the spongiosa from low to high bone turnover conditions. However, despite the potential utility of TSPO expression as an in vivo biomarker of bone turnover in experimental rodent models, our small animal PET imaging data using [18F]fluoride show that even under the condition of a good biological signal-to-noise ratio and high tracer uptake, the currently achievable instrument sensitivity and spatial resolution is unlikely to be sufficient to detect subtle differences in small structures, such as mouse bone. © 2012 Plos One
- Item4D PET iterative deconvolution with spatiotemporal regularization for quantitative dynamic PET imaging(Elsevier, 2015-09-01) Reilhac, A; Charil, A; Wimberley, CA; Angelis, GI; Hamze, H; Callaghan, PD; Garcia, MP; Boisson, F; Ryder, W; Meikle, SR; Grégoire, MCQuantitative measurements in dynamic PET imaging are usually limited by the poor counting statistics particularly in short dynamic frames and by the low spatial resolution of the detection system, resulting in partial volume effects (PVEs). In this work, we present a fast and easy to implement method for the restoration of dynamic PET images that have suffered from both PVE and noise degradation. It is based on a weighted least squares iterative deconvolution approach of the dynamic PET image with spatial and temporal regularization. Using simulated dynamic [11C] Raclopride PET data with controlled biological variations in the striata between scans, we showed that the restoration method provides images which exhibit less noise and better contrast between emitting structures than the original images. In addition, the method is able to recover the true time activity curve in the striata region with an error below 3% while it was underestimated by more than 20% without correction. As a result, the method improves the accuracy and reduces the variability of the kinetic parameter estimates calculated from the corrected images. More importantly it increases the accuracy (from less than 66% to more than 95%) of measured biological variations as well as their statistical detectivity. © 2015 Elsevier Inc.
- ItemAnalytical positron range modelling in heterogeneous media for PET Monte Carlo simulation(IOP Publishing Ltd, 2011-06-07) Lehnert, W; Grégoire, MC; Reilhac, A; Meikle, SRMonte Carlo simulation codes that model positron interactions along their tortuous path are expected to be accurate but are usually slow. A simpler and potentially faster approach is to model positron range from analytical annihilation density distributions. The aims of this paper were to efficiently implement and validate such a method, with the addition of medium heterogeneity representing a further challenge. The analytical positron range model was evaluated by comparing annihilation density distributions with those produced by the Monte Carlo simulator GATE and by quantitatively analysing the final reconstructed images of Monte Carlo simulated data. In addition, the influence of positronium formation on positron range and hence on the performance of Monte Carlo simulation was investigated. The results demonstrate that 1D annihilation density distributions for different isotope–media combinations can be fitted with Gaussian functions and hence be described by simple look-up-tables of fitting coefficients. Together with the method developed for simulating positron range in heterogeneous media, this allows for efficient modelling of positron range in Monte Carlo simulation. The level of agreement of the analytical model with GATE depends somewhat on the simulated scanner and the particular research task, but appears to be suitable for lower energy positron emitters, such as 18F or 11C. No reliable conclusion about the influence of positronium formation on positron range and simulation accuracy could be drawn. © 2011 IOP Publishing LTD
- ItemAttenuation correction for freely moving small animal brain PET studies based on a virtual scanner geometry(IOP Publishing, 2014-09-05) Angelis, GI; Kyme, AZ; Ryder, WJ; Fulton, RR; Meikle, SRAttenuation correction in positron emission tomography brain imaging of freely moving animals is a very challenging problem since the torso of the animal is often within the field of view and introduces a non negligible attenuating factor that can degrade the quantitative accuracy of the reconstructed images. In the context of unrestrained small animal imaging, estimation of the attenuation correction factors without the need for a transmission scan is highly desirable. An attractive approach that avoids the need for a transmission scan involves the generation of the hull of the animal’s head based on the reconstructed motion corrected emission images. However, this approach ignores the attenuation introduced by the animal’s torso. In this work, we propose a virtual scanner geometry which moves in synchrony with the animal’s head and discriminates between those events that traversed only the animal’s head (and therefore can be accurately compensated for attenuation) and those that might have also traversed the animal’s torso. For each recorded pose of the animal’s head a new virtual scanner geometry is defined and therefore a new system matrix must be calculated leading to a time-varying system matrix. This new approach was evaluated on phantom data acquired on the microPET Focus 220 scanner using a custom-made phantom and step-wise motion. Results showed that when the animal’s torso is within the FOV and not appropriately accounted for during attenuation correction it can lead to bias of up to 10% . Attenuation correction was more accurate when the virtual scanner was employed leading to improved quantitative estimates (bias < 2%), without the need to account for the attenuation introduced by the extraneous compartment. Although the proposed method requires increased computational resources, it can provide a reliable approach towards quantitatively accurate attenuation correction for freely moving animal studies. © 2014 Institute of Physics
- ItemAttenuation correction for the large non-human primate brain imaging using microPET(IOP Publishing Ltd, 2010-04-21) Naidoo-Variawa, S; Lehnert, W; Kassiou, M; Banati, RB; Meikle, SRAssessment of the biodistribution and pharmacokinetics of radiopharmaceuticals in vivo is often performed on animal models of human disease prior to their use in humans. The baboon brain is physiologically and neuro-anatomically similar to the human brain and is therefore a suitable model for evaluating novel CNS radioligands. We previously demonstrated the feasibility of performing baboon brain imaging on a dedicated small animal PET scanner provided that the data are accurately corrected for degrading physical effects such as photon attenuation in the body. In this study, we investigated factors affecting the accuracy and reliability of alternative attenuation correction strategies when imaging the brain of a large non-human primate (papio hamadryas) using the microPET Focus 220 animal scanner. For measured attenuation correction, the best bias versus noise performance was achieved using a (57)Co transmission point source with a 4% energy window. The optimal energy window for a (68)Ge transmission source operating in singles acquisition mode was 20%, independent of the source strength, providing bias-noise performance almost as good as for (57)Co. For both transmission sources, doubling the acquisition time had minimal impact on the bias-noise trade-off for corrected emission images, despite observable improvements in reconstructed attenuation values. In a [(18)F]FDG brain scan of a female baboon, both measured attenuation correction strategies achieved good results and similar SNR, while segmented attenuation correction (based on uncorrected emission images) resulted in appreciable regional bias in deep grey matter structures and the skull. We conclude that measured attenuation correction using a single pass (57)Co (4% energy window) or (68)Ge (20% window) transmission scan achieves an excellent trade-off between bias and propagation of noise when imaging the large non-human primate brain with a microPET scanner. © 2010, IOP Publishing LTD.
- ItemCharacterisation of partial volume effect and region-based correction in small animal positron emission tomography (PET) of the rat brain(Elsevier Inc, 2012-05-01) Lehnert, W; Grégoire, MC; Reilhac, A; Meikle, SRAccurate quantification of PET imaging data is required for a useful interpretation of the measured radioactive tracer concentrations. The partial volume effect (PVE) describes signal dilution and mixing due to spatial resolution and sampling limitations, which introduces bias in quantitative results. In the present study we investigated the magnitude of PVE for volumes of interest (VOIs) in the rat brain and the effect of positron range. In simulated 11C-raclopride studies we examined the influence of PVE on time activity curves in striatal and cerebellar VOIs and binding potential estimation. The performance of partial volume correction (PVC) was studied using the region-based geometric transfer matrix (GTM) method including the question of whether a spatially variant point spread function (PSF) is necessary for PVC of a rat brain close to the centre of the field of view. Furthermore, we determined the effect of spillover from activity outside the brain. The results confirmed that PVE is significant in rat brain PET and showed that positron range is an important factor that needs to be included in the PSF. There was considerable bias in time activity curves for the simulated 11C-raclopride studies and significant underestimation of binding potential even for very small centred VOIs. Good activity recovery was achieved with the GTM PVC using a spatially invariant simulated PSF when no activity was present outside the brain. PVC using a simple Gaussian fit point spread function was not sufficiently accurate. Spillover from regions outside the brain had a significant impact on measured activity concentrations and reduced the accuracy of PVC with the GTM method using rat brain regions alone, except for the smallest VOI size but at the cost of increased noise. Voxel-based partial volume correction methods which inherently compensate for spillover from outside the brain might be a more suitable choice. © 2012 Elsevier Inc.
- ItemDetermining glucose metabolism kineticsuUsing 18F-FDG micro-PET/CT(MyJoVE Corporation., 2017-05-02) Cochran, BJ; Ryder, WJ; Parmar, A; Klaeser, K; Reilhac, A; Angelis, GI; Meikle, SR; Barter, PJ; Rye, KAThis paper describes the use of 18F-FDG and micro-PET/CT imaging to determine in vivo glucose metabolism kinetics in mice (and is transferable to rats). Impaired uptake and metabolism of glucose in multiple organ systems due to insulin resistance is a hallmark of type 2 diabetes. The ability of this technique to extract an image-derived input function from the vena cava using an iterative deconvolution method eliminates the requirement of the collection of arterial blood samples. Fitting of tissue and vena cava time activity curves to a two-tissue, three compartment model permits the estimation of kinetic micro-parameters related to the 18F-FDG uptake from the plasma to the intracellular space, the rate of transport from intracellular space to plasma and the rate of 18F-FDG phosphorylation. This methodology allows for multiple measures of glucose uptake and metabolism kinetics in the context of longitudinal studies and also provides insights into the efficacy of therapeutic interventions. © 2022 MyJoVE Corporation
- ItemImaging capabilities of the Inveon SPECT system using single-and multipinhole collimators(Society of Nuclear Medicine and Molecular Imaging, 2013-09-05) Boisson, F; Zahra, D; Parmar, A; Grégoire, MC; Meikle, SR; Hamze, H; Reilhac, AThe Inveon small-animal SPECT system comes with several types of multipinhole collimator plates. We evaluate here the performance measurements of the Inveon SPECT system using 6 different collimators: 3 dedicated for mouse imaging and 3 for rat imaging. Methods: The measured performance parameters include the sensitivity, the spatial resolution using line sources, the ultra-micro Derenzo phantom, the recovery coefficient and the noise measurements using the National Electrical Manufacturers Association NU-4 image quality phantom, obtained with the 2 reconstruction algorithms available with the Inveon Acquisition Workplace, version 1.5—the 3-dimensional ordered-subset expectation maximization (3DOSEM) and the 3-dimensional maximum a posteriori (3DMAP). Further, the overall performance of the system is illustrated by an animal experiment. Results: The results show that the Inveon SPECT scanner offers a spatial resolution, measured at the center of the field of view, ranging from 0.6 to 1 mm with the collimator plates dedicated to mouse imaging and from 1.2 to less than 2 mm with rat collimator plates. The system sensitivity varies from 29 to 404 cps/MBq for mouse collimators and from 53 to 175 cps/MBq for rat collimators. The image quality study showed that 3DMAP allows better noise reduction while preserving the recovery coefficient, compared with other regularization strategies such as the premature termination of the 3DOSEM reconstruction or 3DOSEM followed by gaussian filtering. Conclusion: The acquisition parameters, such as the collimator set and the radius of rotation, offer a wide range of possibilities to apply to a large number of biologic studies. However, special care must be taken because this increase in sensitivity can be offset by image degradation, such as image artifacts caused by projection overlap and statistical noise due to a higher number of iterations required for convergence. 3DMAP allowed better noise reduction while maintaining relatively constant recovery coefficients, as compared with other reconstruction strategies. © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
- ItemImpact of extraneous mispositioned events on motion-corrected brain SPECT images of freely moving animals(American Association of Physicists in Medicine, 2014-08-18) Angelis, GI; Ryder, WJ; Bashar, R; Fulton, RR; Meikle, SRPurpose: Single photon emission computed tomography (SPECT) brain imaging of freely moving small animals would allow a wide range of important neurological processes and behaviors to be studied, which are normally inhibited by anesthetic drugs or precluded due to the animal being restrained. While rigid body motion of the head can be tracked and accounted for in the reconstruction, activity in the torso may confound brain measurements, especially since motion of the torso is more complex (i.e., nonrigid) and not well correlated with that of the head. The authors investigated the impact of mispositioned events and attenuation due to the torso on the accuracy of motion corrected brain images of freely moving mice. Methods: Monte Carlo simulations of a realistic voxelized mouse phantom and a dual compartment phantom were performed. Each phantom comprised a target and an extraneous compartment which were able to move independently of each other. Motion correction was performed based on the known motion of the target compartment only. Two SPECT camera geometries were investigated: a rotating single head detector and a stationary full ring detector. The effects of motion, detector geometry, and energy of the emitted photons (hence, attenuation) on bias and noise in reconstructed brain regions were evaluated. Results: The authors observed two main sources of bias: (a) motion-related inconsistencies in the projection data and (b) the mismatch between attenuation and emission. Both effects are caused by the assumption that the orientation of the torso is difficult to track and model, and therefore cannot be conveniently corrected for. The motion induced bias in some regions was up to 12% when no attenuation effects were considered, while it reached 40% when also combined with attenuation related inconsistencies. The detector geometry (i.e., rotating vs full ring) has a big impact on the accuracy of the reconstructed images, with the full ring detector being more advantageous. Conclusions: Motion-induced inconsistencies in the projection data and attenuation/emission mismatch are the two main causes of bias in reconstructed brain images when there is complex motion. It appears that these two factors have a synergistic effect on the qualitative and quantitative accuracy of the reconstructed images. © 2014 American Association of Physicists in Medicine.
- ItemIn vivo PET imaging with [18F]FDG to explain improved glucose uptake in an apolipoprotein A-I treated mouse model of diabetes(Springer Nature, 2016-05-18) Cochran, BJ; Ryder, WJ; Parmar, A; Tang, S; Reilhac, A; Arthur, A; Charil, A; Hamze, H; Barter, PJ; Kritharides, L; Meikle, SR; Grégoire, MC; Rye, KAType 2 diabetes is characterised by decreased HDL levels, as well as the level of apolipoprotein A-I (apoA-I), the main apolipoprotein of HDLs. Pharmacological elevation of HDL and apoA-I levels is associated with improved glycaemic control in patients with type 2 diabetes. This is partly due to improved glucose uptake in skeletal muscle.© 2016 Springer Nature
- ItemAn investigation of inconsistent projections and artefacts in multi-pinhole SPECT with axially aligned pinholes(IOP Publishing Ltd, 2011-12-07) Kench, PL; Lin, J; Grégoire, MC; Meikle, SRMultiple pinholes are advantageous for maximizing the use of the available field of view (FOV) of compact small animal single photon emission computed tomography (SPECT) detectors. However, when the pinholes are aligned axially to optimize imaging of extended objects, such as rodents, multiplexing of the pinhole projections can give rise to inconsistent datawhich leads to ‘ghost point’ artefacts in the reconstructed volume. A novel four pinhole collimator with a baffle was designed and implemented to eliminate these inconsistent projections. Simulation and physical phantom studies were performed to investigate artefacts from axially aligned pinholes and the efficacy of the baffle in removing inconsistent data and, thus, reducing reconstruction artefacts. SPECT was performed using a Defrise phantom to investigate the impact of collimator design on FOV utilization and axial blurring effects. Multiple pinhole SPECT acquired with a baffle had fewer artefacts and improved quantitative accuracy when compared to SPECT acquired without a baffle. The use of four pinholes positioned in a square maximized the available FOV, increased acquisition sensitivity and reduced axial blurring effects. These findings support the use of a baffle to eliminate inconsistent projection data arising from axially aligned pinholes and improve small animal SPECT reconstructions. © 2011 IOP Publishing LTD
- ItemAn investigation of the challenges in reconstructing PET images of a freely moving animal(Springer Nature, 2013-10-10) Akhta, M; Kyme, AZ; Zhou, V; Fulton, RR; Meikle, SRImaging the brain of a freely moving small animal using positron emission tomography (PET) while simultaneously observing its behaviour is an important goal for neuroscience. While we have successfully demonstrated the use of line-of-response (LOR) rebinning to correct the head motion of confined animals, a large proportion of events may need to be discarded because they either ‘miss’ the detector array after transformation or fall out of the acceptance range of a sinogram. The proportion of events that would have been measured had motion not occurred, so-called ‘lost events’, is expected to be even larger for freely moving animals. Moreover, the data acquisition in the case of a freely moving animal is further complicated by a complex attenuation field. The aims of this study were (a) to characterise the severity of the ‘lost events’ problem for the freely moving animal scenario, and (b) to investigate the relative impact of attenuation correction errors on quantitative accuracy of reconstructed images. A phantom study was performed to simulate the uncorrelated motion of a target and non-target source volume. A small animal PET scanner was used to acquire list-mode data for different sets of phantom positions. The list-mode data were processed using the standard LOR rebinning approach, and multiple frame variants of this designed to reduce discarded events. We found that LOR rebinning caused up to 86 % ‘lost events’, and artifacts that we attribute to incomplete projections, when applied to a freely moving target. This fraction was reduced by up to 18 % using the variant approaches, resulting in slightly reduced image artifacts. The effect of the non-target compartment on attenuation correction of the target volume was surprisingly small. However, for certain poses where the target and non-target volumes are aligned transaxially in the field-of-view, the attenuation problem becomes more complex and sophisticated correction methods will be required. We conclude that there are limitations with the LOR rebinning approach and simplified attenuation correction for freely moving animals requiring the development and validation of more sophisticated approaches. © 2020 Springer Nature Switzerland AG
- ItemOptimisation of PET data processing for a single injection experiment with [11C]Raclopride using a simulations based approach(Society of Nuclear Medicine, 2014-11-05) Wimberley, CA; Angelis, GI; Boisson, F; Callaghan, PD; Fischer, K; Pichler, BJ; Meikle, SR; Grégoire, MC; Reilhac, AObjectives Positron emission tomography (PET) with [11C]Raclopride is an important tool for studying dopamine D2 receptor expression in vivo. [11C]Raclopride PET binding experiments conducted using the Partial Saturation Approach (PSA) (a simple, single injection experiment, Delforge 1995) allow the estimation of receptor density (Bavail) and the in vivo affinity 1/(KD). To achieve accurate and stable parameter estimates, and the ability to detect small changes in these parameters, the impact of the data processing chain should be investigated and optimised. Methods Two groups of PET scans were generated for a Partial Saturation Approach (PSA) experiment using Monte Carlo simulation software with a biological phenomenon inferred between the groups. The kinetic parameters Bavail and KD were estimated and the impact of spatial smoothing, temporal denoising and image resolution recovery on the statistical detectability of change in the estimates was investigated. Results Before optimisation, the inferred Bavail difference between the two groups was underestimated by 42% and detected in 66% of cases (at p<0.05), while a false decrease of KD by 13% was detected in more than 11% of cases. After optimisation, the calculated Bavail difference was underestimated by only 3.7% and detected in 89% of cases, while a false slight increase of KD by 3.7 % was detected in only 2% of cases. Conclusions The use of Monte Carlo generated PET scans allowed the optimisation of the data processing chain in order to reliably estimate and detect changes in the parameters Bavail and KD.
- ItemProjection process modelling for iterative reconstruction of Pinhole SPECT(IEEE, 2010-10-01) Lin, J; Kench, PL; Grégoire, MC; Meikle, SRIn iterative reconstruction of pinhole SPECT data, the forward and back projection processes are often performed using the ray tracing method. Ray tracing is computationally efficient, but it has the drawback of poor reconstruction quality due to the missing voxel effect and textural artefacts. In this paper, the pinhole projection process was modelled starting from consideration of all the main factors affecting pinhole projection, such as voxel shape, penetration of the pinhole edges and detector response. Next, approximations were made to reduce the computational speed and the effect of the approximations on reconstructed image accuracy was evaluated in simulation and phantom experiments and compared with the ray tracing algorithm. When used in conjunction with the ML-EM algorithm, the proposed model improved reconstructed image accuracy compared with the ray tracing method and achieved comparable computational efficiency. Therefore, the proposed projection model is a practical alternative to the ray tracing algorithm for pinhole SPECT reconstruction.© 2010, Institute of Electrical and Electronics Engineers (IEEE)
- ItemScatter correction for large non-human primate brain imaging using microPET(Institute of Physics, 2011-04-07) Naidoo-Variawa, S; Lehnert, W; Banati, RB; Meikle, SRThe baboon is well suited to pre-clinical evaluation of novel radioligands for positron emission tomography (PET). We have previously demonstrated the feasibility of using a high resolution animal PET scanner for this application in the baboon brain. However, the non-homogenous distribution of tissue density within the head may give rise to photon scattering effects that reduce contrast and compromise quantitative accuracy. In this study, we investigated the magnitude and distribution of scatter contributing to the final reconstructed image and its variability throughout the baboon brain using phantoms and Monte Carlo simulated data. The scatter fraction is measured up to 36% at the centre of the brain for a wide energy window (350–650 keV) and 19% for a narrow (450–650 keV) window. We observed less than 3% variation in the scatter fraction throughout the brain and found that scattered events arising from radioactivity outside the field of view contribute less than 1% of measured coincidences. In a contrast phantom, scatter and attenuation correction improved contrast recovery compared with attenuation correction on its own and reduced bias to less than 10% at the expense of the reduced signal-to-noise ratio. We conclude that scatter correction is a necessary step for ensuring high quality measurements of the radiotracer distribution in the baboon brain with a microPET scanner, while it is not necessary to model out of field of view scatter or a spatially variant scatter function. © 2011, Institute of Physics
- ItemSimulation-based optimisation of the PET data processing for partial saturation approach protocols(Elsevier B.V., 2014-08-15) Wimberley, CA; Angelis, GI; Boisson, F; Callaghan, PD; Fischer, K; Pichler, BJ; Meikle, SR; Grégoire, MC; Reilhac, APositron emission tomography (PET) with [11C]Raclopride is an important tool for studying dopamine D2 receptor expression in vivo. [11C]Raclopride PET binding experiments conducted using the Partial Saturation Approach (PSA) allow the estimation of receptor density (Bavail) and the in vivo affinity appKD. The PSA is a simple, single injection, single scan experimental protocol that does not require blood sampling, making it ideal for use in longitudinal studies. In this work, we generated a complete Monte Carlo simulated PET study involving two groups of scans, in between which a biological phenomenon was inferred (a 30% decrease of Bavail), and used it in order to design an optimal data processing chain for the parameter estimation from PSA data. The impact of spatial smoothing, noise removal and image resolution recovery technique on the statistical detection was investigated in depth. We found that image resolution recovery using iterative deconvolution of the image with the system point spread function associated with temporal data denoising greatly improves the accuracy and the statistical reliability of detecting the imposed phenomenon. Before optimisation, the inferred Bavail variation between the two groups was underestimated by 42% and detected in 66% of cases, while a false decrease of appKD by 13% was detected in more than 11% of cases. After optimisation, the calculated Bavail variation was underestimated by only 3.7% and detected in 89% of cases, while a false slight increase of appKD by 3.7% was detected in only 2% of cases. We found during this investigation that it was essential to adjust a factor that accounts for difference in magnitude between the non-displaceable ligand concentrations measured in the target and in the reference regions, for different data processing pathways as this ratio was affected by different image resolutions. © 2014 Elsevier B.V..
- ItemTrishomocubanes: novel σ ligands modulate cocaine-induced behavioural effects(Elsevier Science B.V., 2007-01-19) Liu, X; Banister, SD; Christie, MJ; Banati, RB; Meikle, SR; Coster, MJ; Kassiou, MTrishomocubane analogues TC1 (N-(3′-fluorophenyl)ethyl-4-azahexacyclo [5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ol) and TC4 (N-(3′-fluorophenyl)methyl-4-azahexacyclo [5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ol) were evaluated for their modulatory effects on locomotor activity as well as interactions with cocaine-induced responses. TC1 and TC4 have high affinity and moderate to high selectivity for σ1 (Ki = 10 nM, σ1/σ2 = 0.03) and σ2 (Ki = 20 nM, σ1/σ2 = 7.6) receptor subtypes respectively. Both compounds have negligible affinity for the dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters. In behavioural studies, TC1 produced a dose-related inhibition in spontaneous locomotor activity measured in a Digiscan apparatus. TC1 attenuated the stimulatory locomotor effect of 20 mg/kg cocaine with a half-maximal depressant activity (ID50) of 38.6 mg/kg. TC1 (dose range of 25 to 100 mg/kg) also partially substituted for the effect of cocaine (10 mg/kg) in a discriminative stimulus task, involving the trained discrimination between cocaine and saline using a two-lever choice method. Following a dose of 50 mg/kg TC1, a maximum of 31% substitution was reached. The response rate was reduced to 56% of vehicle control following a TC1 dose of 100 mg/kg. These behavioural effects suggest that TC1 can act as an antagonist via the σ1 receptor. In contrast to TC1, TC4 produced a stimulant effect in locomotor activity with the ED50 estimated at 0.94 mg/kg. In addition, TC4 failed to inhibit cocaine-induced stimulation; neither did it substitute for the discriminative stimulus effects of cocaine. TC4 thus appears to interact predominantly with the σ2 receptor subtype (σ1/σ2 = 7.6) which may result in dopamine stimulation independent of the effects of cocaine. The differential effect of TC1 and TC4 warrants further study of the mechanism of these actions. Present data also suggests a potential role for trishomocubane analogues in developing medication or research tools for cocaine addiction. © 2007, Elsevier Ltd.