Imaging of the striatal and extrastriatal dopamine transporter with (18)F-LBT-999: quantification, biodistribution, and radiation dosimetry in nonhuman primates.

UNLABELLED: The aim of this study was to evaluate the quantification, biodistribution, and radiation dosimetry of the novel dopamine transporter (DAT) radioligand (18)F-(2S,3S)-methyl 8-((E)-4-fluorobut-2-en-1-yl)-3-(p-tolyl)-8-azabicyclo[3.2.1]octane-2-carboxylate ((18)F-LBT-999) in nonhuman primates. METHODS: The brain study was conducted in 4 female rhesus monkeys. PET measurements were conducted for 243 min using the high-resolution research tomograph (HRRT) with the measurement of the metabolite-corrected arterial input function and protein binding. Quantification was performed with kinetic analysis using 2-tissue- and 1-tissue-compartment models, with Logan graphical analysis and with different reference tissue models. The outcome measures were total distribution volume (V(T)), nondisplaceable distribution volume (V(ND)), binding potential relative to the free concentration of radioligand in plasma (BP(F)), and binding potential relative to the concentration of nondisplaceable radioligand in tissue (BP(ND)) = V(T) - V(ND)/V(ND) using the cerebellum as a reference region. For the biodistribution and radiation dosimetry, 2 female cynomolgus monkeys were studied. Whole-body PET scans were obtained using a PET/CT system for approximately 250 min. Estimates of the absorbed radiation dose in humans were calculated using OLINDA/EXM software. RESULTS: (18)F-LBT-999 showed good brain uptake (300% standardized uptake value) and regional distribution according to known DAT density. The 2-tissue-compartment model was the preferred model for the quantification. Late peak equilibrium (120-140 min) and slow washout were observed in the striatum, with high variability of V(T), BP(F), and BP(ND). When the different models were compared with the 2-tissue-compartment model, the underestimation of V(T) or BP(ND) was larger in the caudate and putamen than in the midbrain and thalamus. The reference tissue models were suitable for the quantification. The whole-body distribution study showed that the main routes of excretion of (18)F-LBT-999 were the urinary and gastrointestinal systems, with the bladder being the critical organ. Accumulation of (18)F-LBT-999 was found in the bone and skull, with a relatively high dose estimated for the osteogenic cells. The range of calculated effective dose was 0.021-0.022 mSv/MBq. CONCLUSION: (18)F-LBT-999 seemed to be a suitable PET radioligand for the DAT quantification, particularly for extrastriatal regions. The skull uptake did not seem to be a limitation for brain imaging. The calculated dosimetry estimates based on data in nonhuman primates seemed comparable with those of other clinically used (18)F-labeled radioligands, for example, (18)F-FDG (0.024-0.027 mSv/MBq).

Effects of EMDR psychotherapy on 99mTc-HMPAO distribution in occupation-related post-traumatic stress disorder.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a derangement of mood control with involuntary, emotionally fraught recollections that may follow deep psychological trauma in susceptible individuals. This condition is treated with pharmacological and/or cognitive therapies as well as psychotherapy with eye movement desensitization and reprocessing (EMDR). However, only a very limited number of studies have been published dealing with work-related PTSD, and investigations on the effect of treatment on cerebral blood flow represent an even smaller number. AIM: To investigate the short-term outcome of occupation-related PTSD after EMDR therapy by 99mTc-HMPAO SPECT. METHOD: Fifteen patients, either train drivers suffering from PTSD after having been unintentionally responsible for a person-under-train accident or employees assaulted in the course of duty, were recruited for the study. 99mTc-HMPAO SPECT was performed on these patients both before and after EMDR therapy while they listened to a script portraying the traumatic event. Tracer distribution analysis was then carried out at volume of interest (VOI) level using a three-dimensional standardized brain atlas, and at voxel level by SPM. The CBF data of the 15 patients were compared before and after treatment as well as with those of a group of 27 controls who had been exposed to the same psychological traumas without developing PTSD. RESULTS: At VOI analysis significant CBF distribution differences were found between controls and patients before and after treatment (P=0.023 and P=0.0039, respectively). Eleven of the 15 patients responded to treatment, i.e., following EMDR they no longer fulfilled the DSM-IV criteria for PTSD. When comparing only the eleven responders with the controls, the significant group difference found before EMDR (P=0.019) disappeared after treatment. Responders and non-responders showed after therapy significant regional differences in frontal, parieto-occipital and visual cortex and in hippocampus. SPM analysis showed significant uptake differences between patients and controls in the orbitofrontal cortex (Brodmann 11) and the temporal pole (Brodmann 38) both before and after treatment. A significant tracer distribution difference present before treatment in the uncus (Brodmann 36) disappeared after treatment, while a significant difference appeared in the lateral temporal lobe (Brodmann 21). CONCLUSION: Significant 99mTc-HMPAO uptake regional differences were found, mainly in the peri-limbic cortex, between PTSD patients and controls exposed to trauma but not developing PTSD. Tracer uptake differences between responders and patients not responding to EMDR were found after treatment suggesting a trend towards normalization of tracer distribution after successful therapy. These findings in occupational related PTSD are consistent with previously described effects of psychotherapy on anxiety disorders.