In vivo imaging of the 18-kDa translocator protein (TSPO) with [18F]FEDAA1106 and PET does not show increased binding in Alzheimer’s disease patients

Purpose

Imaging the 18-kDa translocator protein (TSPO) is considered a potential tool for in vivo evaluation of microglial activation and neuroinflammation in the early stages of Alzheimer’s disease (AD). ((R)-1-(2-chlorophenyl)-N-[¹¹C]-methyl-N-(1-methylpropyl)-3-isoquinoline caboxamide ([¹¹C]-(R)-PK11195) has been widely used for PET imaging of TSPO and, despite its low specific-to-nondisplaceable binding ratio, increased TSPO binding has been shown in AD patients. The high-affinity radioligand N-(5-fluoro-2-phenoxyphenyl)-N-(2-[¹⁸F]fluoroethyl-5-methoxybenzyl)acetamide ([¹⁸F]FEDAA1106) has been developed as a potential in vivo imaging tool for better quantification of TSPO binding. The aim of this study was to quantify in vivo binding of [¹⁸F]FEDAA1106 to TSPO in control subjects and AD patients.

Methods

Seven controls (five men, two women, age 68±3 years, MMSE score 29±1) and nine AD patients (six men, three women, age 69±4 years, MMSE score 25±3) were studied with [¹⁸F]FEDAA1106. PET measurements were performed on an ECAT EXACT HR system (Siemens Medical Solutions) in two 60-min dynamic PET sessions with a 30-min interval between sessions. Arterial blood radioactivity was measured using an automated blood sampling system for the first 5 min and using manually drawn samples thereafter. Quantification was performed using both kinetic analysis based on a two-tissue compartment model and Logan graphical analysis. Outcome measures were total distribution volume (V _T) and binding potential (BP _ND=k ₃/k ₄). An estimate of nondisplaceable distribution volume was obtained with the Logan graphical analysis using the first 15 min of PET measurements (V _{ND 1-15 min}). Binding potential (BP _ND) was also calculated as: V _T/V _{ND 1-15 min} ? 1.

Results

No statistically significant differences in V _T, k ₃/k ₄ or BP _ND were observed between controls and AD patients.

Conclusion

This study suggests that TSPO imaging with [¹⁸F]FEDAA1106 does not enable the detection of microglial activation in AD.     

The translocator protein ligand [18F]DPA-714 images glioma and activated microglia in vivo

Purpose

In recent years there has been an increase in the development of radioligands targeting the 18-kDa translocator protein (TSPO). TSPO expression is well documented in activated microglia and serves as a biomarker for imaging neuroinflammation. In addition, TSPO has also been reported to be overexpressed in a number of cancer cell lines and human tumours including glioma. Here we investigated the use of [¹⁸F]DPA-714, a new TSPO positron emission tomography (PET) radioligand to image glioma in vivo.

Methods

We studied the uptake of [¹⁸F]DPA-714 in three different rat strains implanted with 9L rat glioma cells: Fischer (F), Wistar (W) and Sprague Dawley (SD) rats. Dynamic [¹⁸F]DPA-714 PET imaging, kinetic modelling of PET data and in vivo displacement studies using unlabelled DPA-714 and PK11195 were performed. Validation of TSPO expression in 9L glioma cell lines and intracranial 9L gliomas were investigated using Western blotting and immunohistochemistry of brain tissue sections.

Results

All rats showed significant [¹⁸F]DPA-714 PET accumulation at the site of 9L tumour implantation compared to the contralateral brain hemisphere with a difference in uptake among the three strains (F?>?W?>?SD). The radiotracer showed high specificity for TSPO as demonstrated by the significant reduction of [¹⁸F]DPA-714 binding in the tumour after administration of unlabelled DPA-714 or PK11195. TSPO expression was confirmed by Western blotting in 9L cells in vitro and by immunohistochemistry ex vivo.

Conclusion

The TSPO radioligand [¹⁸F]DPA-714 can be used for PET imaging of intracranial 9L glioma in different rat strains. This preclinical study demonstrates the feasibility of employing [¹⁸F]DPA-714 as an alternative radiotracer to image human glioma.     

Binding of <Superscript>11</Superscript>C-Pittsburgh compound-B correlated with white matter injury in hypertensive small vessel disease

Objective

¹¹C-Pittsburgh compound-B (¹¹C-PIB) positron emission tomography (PET) is used to visualize and quantify amyloid deposition in the brain cortex in pathological conditions such as Alzheimer’s disease (AD). Intense ¹¹C-PIB retention is also observed in the white matter (WM) of both healthy individuals and AD patients. However, the clinical implications of this retention in brain WM have not been clarified. We investigated the relationship between the extent of white matter lesions (WMLs) and the binding potential of ¹¹C-PIB (BP_ND) in the WM in patients with hypertensive small vessel disease. We further examined the relationship between the extent of WMLs and BP_ND in WML and in normal-appearing white matter (NAWM).

Methods

Twenty-one hypertensive vasculopathy patients, without AD and major cerebral arterial stenosis and/or occlusion, were enrolled (9 women, 68?±?7 years). Regions of WML and NAWM were extracted using magnetization-prepared rapid gradient-echo and fluid-attenuated inversion recovery of magnetic resonance images. Volumes of interest (VOIs) were set in the cortex-subcortex, basal ganglia, and centrum semiovale (CS). BP_ND in the cortex-subcortex, basal ganglia, CS, WML, and NAWM were estimated on ¹¹C-PIB PET using Logan graphical analysis with cerebellar regions as references. The relationships between WML volume and BP_ND in each region were examined by linear regression analysis.

Results

BP_ND was higher in the CS and basal ganglia than in the cortex-subcortex regions. WML volume had a significant inverse correlation with BP_ND in the CS (Slope?=??0.0042, R ² ?=?0.44, P?<?0.01). For intra WM comparison, BP_ND in NAWM was significantly higher than that in WML. In addition, although there were no correlations between WML volume and BP_ND in WML, WML volume was significantly correlated inversely with BP_ND in NAWM (Slope?=??0.0017, R ² ?=?0.26, P?=?0.02).

Conclusions

¹¹C-PIB could be a marker of not only cortical amyloid-β deposition but also WM injury accompanying the development of WMLs in hypertensive small vessel disease.

     

Validation of reference tissue modelling for [11C]flumazenil positron emission tomography following head injury

Objective

[¹¹C]Flumazenil ([¹¹C]FMZ) positron emission tomography (PET) can be used as a measure of neuronal loss. The purpose of this study was to validate reference tissue kinetic modelling of [¹¹C]FMZ PET within a group of patients with head injury.

Methods

Following earlier studies, the pons was used as the reference region. PET scans were performed on 16 controls and 11 patients at least 6 months following injury, each of whom also had arterial blood sampling to provide whole blood and metabolite-corrected plasma input functions. Regional non-displaceable binding potentials (BP_ND) were calculated from five reference tissue models and compared to BP_ND from arterial input models. For the patients, the regions included a peri-lesional region of interest (ROI).

Results

Total distribution volume of the pons was not significantly different between control and patient groups (P = 0.24). BP_ND from all the reference tissue approaches correlated well with BP_ND from the plasma input models for both controls (r ² = 0.98–1.00; P < 0.001) and patients (r ² = 0.99–1.00; P < 0.001). For the peri-lesional regions (n = 11 ROI values), the correlation was also high (r ² = 0.91).

Conclusions

These results indicate that reference tissue modelling with the pons as the reference region is valid for [¹¹C]FMZ PET in head-injured patients at 6 months following injury within both normal appearing and peri-lesional brain regions.     

In vivo imaging of neuroinflammation in the rodent brain with [11C]SSR180575, a novel indoleacetamide radioligand of the translocator protein (18?kDa)

Purpose

Neuroinflammation is involved in neurological disorders through the activation of microglial cells. Imaging of neuroinflammation with radioligands for the translocator protein (18 kDa) (TSPO) could prove to be an attractive biomarker for disease diagnosis and therapeutic evaluation. The indoleacetamide-derived 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, SSR180575, is a selective high-affinity TSPO ligand in human and rodents with neuroprotective effects.

Methods

Here we report the radiolabelling of SSR180575 with ¹¹C and in vitro and in vivo imaging in an acute model of neuroinflammation in rats.

Results

The image contrast and the binding of [¹¹C]SSR180575 are higher than that obtained with the isoquinoline-based TSPO radioligand, [¹¹C]PK11195. Competition studies demonstrate that [¹¹C]SSR180575 has high specific binding for the TSPO.

Conclusion

[¹¹C]SSR180575 is the first PET radioligand for the TSPO based on an indoleacetamide scaffold designed for imaging neuroinflammation in animal models and in the clinic.     

In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer��s disease

Purpose

Amyloid ?? protein (A??) is known as a pathological substance in Alzheimer??s disease (AD) and is assumed to coexist with a degree of activated microglia in the brain. However, it remains unclear whether these two events occur in parallel with characteristic hypometabolism in AD in vivo. The purpose of the present study was to clarify the in vivo relationship between A?? accumulation and neuroinflammation in those specific brain regions in early AD.

Methods

Eleven nootropic drug-na?ve AD patients underwent a series of positron emission tomography (PET) measurements with [¹¹C](R)PK11195, [¹¹C]PIB and [¹⁸F]FDG and a battery of cognitive tests within the same day. The binding potentials (BPs) of [¹¹C](R)PK11195 were directly compared with those of [¹¹C]PIB in the brain regions with reduced glucose metabolism.

Results

BPs of [¹¹C](R)PK11195 and [¹¹C]PIB were significantly higher in the parietotemporal regions of AD patients than in ten healthy controls. In AD patients, there was a negative correlation between dementia score and [¹¹C](R)PK11195 BPs, but not [¹¹C]PIB, in the limbic, precuneus and prefrontal regions. Direct comparisons showed a significant negative correlation between [¹¹C](R)PK11195 and [¹¹C]PIB BPs in the posterior cingulate cortex (PCC) (p?<?0.05, corrected) that manifested the most severe reduction in [¹⁸F]FDG uptake.

Conclusion

A lack of coupling between microglial activation and amyloid deposits may indicate that A?? accumulation shown by [¹¹C]PIB is not always the primary cause of microglial activation, but rather the negative correlation present in the PCC suggests that microglia can show higher activation during the production of A?? in early AD.     

Test-retest reproducibility of dopamine D2/3 receptor binding in human brain measured by PET with [11C]MNPA and [11C]raclopride

Purpose

Dopamine D_2/3 receptors (D_2/3Rs) have two affinity states for endogenous dopamine, referred to as high-affinity state (D_2/3 ^HIGH), which has a high affinity for endogenous dopamine, and low-affinity state (D_2/3 ^LOW). The density of D_2/3 ^HIGH can be measured with (R)-2-¹¹CH₃O-N-n-propylnorapomorphine ([¹¹C]MNPA), while total density of D_2/3 ^HIGH and D_2/3 ^LOW (D_2/3Rs) can be measured with [¹¹C]raclopride using positron emission tomography (PET). Thus, the ratio of the binding potential (BP) of [¹¹C]MNPA to that of [¹¹C]raclopride ([¹¹C]MNPA/[¹¹C]raclopride) may reflect the proportion of the density of D_2/3 ^HIGH to that of D_2/3Rs. In the caudate and putamen, [¹¹C]MNPA/[¹¹C]raclopride reflects the proportion of the density of D₂ ^HIGH to that of D₂Rs. To evaluate the reliability of the PET paradigm with [¹¹C]MNPA and [¹¹C]raclopride, we investigated the test-retest reproducibility of non-displaceable BP (BP _ND) measured with [¹¹C]MNPA and of [¹¹C]MNPA/[¹¹C]raclopride in healthy humans.

Methods

Eleven healthy male volunteers underwent two sets of PET studies on separate days that each included [¹¹C]MNPA and [¹¹C]raclopride scans. BP _ND values in the caudate and putamen were calculated. Test-retest reproducibility of BP _ND of [¹¹C]MNPA and [¹¹C]MNPA/[¹¹C]raclopride was assessed by intra-subject variability (absolute variability) and test-retest reliability (intraclass correlation coefficient: ICC).

Results

The absolute variability of [¹¹C]MNPA BP _ND was 5.30?±?3.96 % and 12.3?±?7.95 % and the ICC values of [¹¹C]MNPA BP _ND were 0.72 and 0.82 in the caudate and putamen, respectively. The absolute variability of [¹¹C]MNPA/[¹¹C]raclopride was 6.11?±?3.68 % and 11.60?±?5.70 % and the ICC values of [¹¹C]MNPA/[¹¹C]raclopride were 0.79 and 0.80 in the caudate and putamen, respectively.

Conclusion

In the present preliminary study, the test-retest reproducibility of BP _ND of [¹¹C]MNPA and of [¹¹C]MNPA/[¹¹C]raclopride was reliable in the caudate and putamen.     

PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714

Purpose

The inflammatory response in injured brain parenchyma after traumatic brain injury (TBI) is crucial in the pathological process. In order to follow microglia activation and neuroinflammation after TBI, we performed PET imaging in a rat model of TBI using ¹⁸F-labeled DPA-714, a ligand of the 18-kDa translocator protein (TSPO).

Methods

TBI was induced in male SD rats by a controlled cortical impact. The success of the TBI model was confirmed by MRI. [¹⁸F]DPA-714 was synthesized using a slightly modified TRACERLab FX-FN module and an automated procedure. In vivo PET imaging was performed at different time points after surgery using an Inveon small-animal PET scanner. The specificity of [¹⁸F]DPA-714 was confirmed by a displacement study with an unlabeled competitive TSPO ligand, PK11195. Ex vivo autoradiography as well as immunofluorescence staining was carried out to confirm the in vivo PET results.

Results

Both in vivo T₂-weighted MR images and ex vivo TTC staining results revealed successful establishment of the TBI model. Compared with the sham-treated group, [¹⁸F]DPA-714 uptake was significantly higher in the injured brain area on PET images. Increased lesion-to-normal ratios of [¹⁸F]DPA-714 were observed in the brain of TBI rats on day 2 after surgery. Ratios peaked around day 6 (2.65?±?0.36) and then decreased gradually to nearly normal levels on day 28. The displacement study using PK11195 confirmed the specific binding of [¹⁸F]DPA-714 to TSPO. The results of ex vivo autoradiography were consistent with in vivo PET results. Immunofluorescence staining showed the time course of TSPO expression after TBI and the temporal and the spatial distribution of microglia in the damaged brain area.

Conclusion

TSPO-targeted PET using [¹⁸F]DPA-714 as the imaging probe can be used to dynamically monitor the inflammatory response after TBI in a noninvasive manner. This method will not only facilitate a better understanding of the inflammatory process after TBI, but also provide a useful in vivo monitoring strategy for antiinflammation therapy of TBI.     

Decreased cerebral ��4��2* nicotinic acetylcholine receptor availability in patients with mild cognitive impairment and Alzheimer��s disease assessed with positron emission tomography

Purpose

Postmortem studies indicate a loss of nicotinic acetylcholine receptor (nAChRs) in Alzheimer??s disease (AD). In order to establish whether these changes in the cholinergic system occur at an early stage of AD, we carried out positron emission tomography (PET) with a specific radioligand for the ??4??2* nicotinic acetylcholine receptor (??4??2* nAChR) in patients with mild to moderate AD and in patients with amnestic mild cognitive impairment (MCI), who have a high risk to progress to AD.

Methods

Nine patients with moderate AD, eight patients with MCI and seven age-matched healthy controls underwent 2-[¹⁸F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[¹⁸F]FA-85380) PET. After coregistration with individual magnetic resonance imaging the binding potential (BP_ND) of 2-[¹⁸F]FA-85380 was calculated using either the corpus callosum or the cerebellum as reference regions. PET data were analysed by region of interest analysis and by voxel-based analysis.

Results

Both patients with AD and MCI showed a significant reduction in 2-[¹⁸F]FA-85380 BP_ND in typical AD-affected brain regions. Thereby, the corpus callosum was identified as the most suitable reference region. The 2-[¹⁸F]FA-85380 BP_ND correlated with the severity of cognitive impairment. Only MCI patients that converted to AD in the later course (n?=?5) had a reduction in 2-[¹⁸F]FA-85380 BP_ND.

Conclusion

2-[¹⁸F]FA-85380 PET appears to be a sensitive and feasible tool for the detection of a reduction in ??4??2* nAChRs which seems to be an early event in AD. In addition, 2-[¹⁸F]FA-85380 PET might give prognostic information about a conversion from MCI to AD.     

The correlation between striatal and cortical binding ratio of <Superscript>11</Superscript>C-PiB-PET in amyloid-uptake-positive patients

Purpose

In subjects with amyloid deposition, striatal accumulation of ¹¹C-Pittsburgh compound B (PiB) demonstrated by positron emission tomography (PET) is related to the stage of Alzheimer’s disease (AD). In this study, we investigated the correlation between striatal and cortical non-displaceable binding potential (BP_ND).

Methods

Seventy-three subjects who complained of cognitive disturbance underwent dynamic PiB-PET studies and showed positive PiB accumulation were retrospectively selected. These subjects included 34 AD, 26 mild cognitive impairment, 2 frontotemporal lobar degeneration, 2 Parkinson’s disease, 5 dementia with Lewy bodies, and 4 undefined diagnosis patients. Individual BP_ND images were produced from the dynamic data of the PiB-PET study, and voxel-based analyses were performed to estimate the correlations between striatal and other regional cortical BP_ND measures.

Results

There were highly significant correlations between striatal and prefrontal BP_ND, with the highest correlation being demonstrated in left Brodmann area 11. We found that almost all of the high cortical BP_ND values correlated with striatal BP_ND values, with the exception of the occipital cortex with low correlation.

Conclusion

Our study demonstrated positive correlations in amyloid deposits between the striatum and other cortical areas with functional and anatomical links. The amyloid distribution in the brain is not random, but spreads following the functional and anatomical connections.

     

Detection and quantification of remote microglial activation in rodent models of focal ischaemia using the TSPO radioligand CLINDE

Purpose

Neuroinflammation is involved in stroke pathophysiology and might be imaged using radioligands targeting the 18 kDa translocator protein (TSPO).

Methods

We studied microglial reaction in brain areas remote from the primary lesion site in two rodent models of focal cerebral ischaemia (permanent or transient) using [¹²⁵I]-CLINDE, a promising TSPO single photon emission computed tomography radioligand.

Results

In a mouse model of permanent middle cerebral artery occlusion (MCAO), ex vivo autoradiographic studies demonstrated, besides in the ischaemic territory, accumulation of [¹²⁵I]-CLINDE in the ipsilateral thalamus with a binding that progressed up to 3 weeks after MCAO. [¹²⁵I]-CLINDE binding markedly decreased in animals pre-injected with either unlabelled CLINDE or PK11195, while no change was observed with flumazenil pre-treatment, demonstrating TSPO specificity. In rats subjected to transient MCAO, [¹²⁵I]-CLINDE binding in the ipsilateral thalamus and substantia nigra pars reticulata (SNr) was significantly higher than that in contralateral tissue. Moreover, [¹²⁵I]-CLINDE binding in the thalamus and SNr was quantitatively correlated to the ischaemic volume assessed by MRI in the cortex and striatum, respectively.

Conclusion

Clinical consequences of secondary neuronal degeneration in stroke might be better treated thanks to the discrimination of neuronal processes using in vivo molecular imaging and potent TSPO radioligands like CLINDE to guide therapeutic interventions.     

In vivo imaging of neuroinflammation: a comparative study between [18F]PBR111, [11C]CLINME and [11C]PK11195 in an acute rodent model

Purpose

The key role of neuroinflammation in acute and chronic neurological disorders has stimulated the search for specific radiotracers targeting the peripheral benzodiazepine receptor (PBR)/18 kDa translocator protein (TSPO), a hallmark of neuroinflammation. Here we evaluate the new radiotracer for positron emission tomography (PET) [¹⁸F]PBR111 in a rodent model of acute inflammation and compare it with [¹¹C]CLINME, an ¹¹C-labelled tracer of the same chemical family, and with the isoquinolinic carboxamide [¹¹C]PK11195.

Methods

We studied radiometabolites by HPLC, in vitro binding by autoradiography and in vivo brain kinetics as well as in vivo specificity of binding using PET imaging.

Results

We show that this radiotracer has a high in vitro specificity for PBR/TSPO versus central benzodiazepine receptors, as reflected by the drastic reduction of its binding to target tissue by addition of PK11195 or PBR111, while addition of flumazenil does not affect binding. Only intact [¹⁸F]PBR111 is detected in brain up to 60 min after i.v. injection, and PET imaging shows an increased uptake in the lesion as compared to the contralateral side as early as 6 min after injection. Administration of an excess of PK11195 and PBR111, 20 min after [¹⁸F]PBR111 administration, induces a rapid and complete displacement of [¹⁸F]PBR111 binding from the lesion. Modelling of the PET data using the simplified reference tissue model showed increased binding potential (BP) in comparison to [¹¹C]PK11195.

Conclusion

[¹⁸F]PBR111 is a metabolically stable tracer with a high specific in vitro and in vivo binding to TSPO. In addition, considering the longer half-life of ¹⁸F over ¹¹C, these results support [¹⁸F]PBR111 as a promising PET tracer of the PBR/TSPO for neuroinflammation imaging.     

Improved mapping and quantification of serotonin transporter availability in the human brainstem with the HRRT

Purpose

The serotonin system is involved in many physiological functions and clinical conditions. Serotonergic neurons originate from the raphe nuclei in the brainstem, and reliable estimates of receptor/transporter availability in the raphe in vivo are thus of interest. Though positron emission tomography (PET) can be used to quantify receptor distribution in the brain, high noise levels prevent reliable estimation of radioligand binding in small regions such as the raphe. For this purpose, parametric imaging in combination with high-resolution PET systems may provide images with reduced noise levels and sufficient contrast for reliable quantification. This study examined the potential to evaluate radioligand binding in brainstem nuclei, and assessed the effect of improved resolution on the outcome measures.

Methods

For comparative purposes, radioligand binding was measured with an ECAT EXACT HR PET system (resolution about 4.5 mm FWHM) and a high-resolution research tomograph (HRRT) system (resolution about 1.5 mm FWHM). Six subjects were examined with both systems on the same day using the serotonin transporter radioligand [¹¹C]MADAM. Parametric images of binding potential (BP _ND) were obtained using a wavelet-aided approach. Regions of interest (ROIs) were delineated using a threshold-based semiautomatic delineation procedure for five brainstem structures. Regional BP _ND values were estimated by applying the ROIs to the parametric images, and the percentage difference in BP _ND between the systems was calculated.

Results

Signals for [¹¹C]MADAM binding were obtained for all five brainstem structures. Overall, the HRRT provided 30–40 % higher BP _ND values than the HR (p?=?0.0017), independent of thresholds used in the ROI delineation procedure.

Conclusion

The methodology used enabled the estimation of [¹¹C]MADAM binding in the small nuclei of the brainstem. Differences in the BP _ND values calculated using data from the two systems were mainly attributable to their differing resolutions. The estimated BP _ND values provided lower across-subject variability than those previously obtained using compartment analysis. This procedure may therefore facilitate quantitative studies of receptor/transporter availability in the brainstem.     

Human biodistribution and radiation dosimetry of 11C-(R)-PK11195, the prototypic PET ligand to image inflammation

Purpose  

The positron emission tomography (PET) radiotracer ¹¹C-(R)-PK11195 allows the in vivo imaging in humans of the translocator protein 18 kDa (TSPO), previously called peripheral benzodiazepine receptor (PBR), a marker of inflammation. Despite its widespread use, the radiation burden associated with ¹¹C-(R)-PK11195 in humans is not known. To examine this, we performed dynamic whole-body imaging with PET and ¹¹C-(R)-PK11195 in healthy humans.     

Pharmacokinetic analysis of [18F]FAZA in non-small cell lung cancer patients

Purpose

[¹⁸F]Fluoroazomycin arabinoside (FAZA) is a positron emission tomography (PET) tracer developed to enable identification of hypoxic regions within a tumour. The aims of this study were to determine the optimal kinetic model along with validation of using alternatives to arterial blood sampling for analysing [¹⁸F]FAZA studies and to assess the validity of simplified analytical methods.

Methods

Dynamic 70-min [¹⁸F]FAZA PET/CT scans were obtained from nine non-small cell lung cancer patients. Continuous arterial blood sampling, together with manual arterial and venous sampling, was performed to derive metabolite-corrected plasma input functions. Volumes of interest (VOIs) were defined for tumour, healthy lung muscle and adipose tissue generating [¹⁸F]FAZA time-activity curves (TACs). TACs were analysed using one- and two-tissue compartment models using both metabolite-corrected blood sampler plasma input functions (BSIF) and image-derived plasma input functions (IDIF).

Results

The reversible two-tissue compartment model with blood volume parameter (2T4k+V_B) best described kinetics of [¹⁸F]FAZA in tumours. Volumes of distribution (V_T) obtained using IDIF correlated well with those derived using BSIF (R ²?=?0.82). Venous samples yielded the same radioactivity concentrations as arterial samples for times >50 min post-injection (p.i.). In addition, both plasma to whole blood ratios and parent fractions were essentially the same for venous and arterial samples. Both standardised uptake value (SUV), normalised to lean body mass, and tumour to blood ratio correlated well with V_T (R ²?=?0.77 and R ²?=?0.87, respectively, at 50–60 min p.i.), although a bias was observed at low V_T.

Conclusion

The 2T4k+V_B model provided the best fit to the dynamic [¹⁸F]FAZA data. IDIF with venous blood samples can be used as input function. Further data are needed to validate the use of simplified methods.     

Quantification of (<Emphasis Type="Italic">R</Emphasis>)-[<Superscript>11</Superscript>C]PK11195 binding in rheumatoid arthritis

Purpose  Rheumatoid arthritis (RA) involves migration of macrophages into inflamed areas. (R)-[¹¹C]PK11195 binds to peripheral benzodiazepine receptors, expressed on macrophages, and may be used to quantify inflammation using positron emission tomography (PET). This study evaluated methods for the quantification of (R)-[¹¹C]PK11195 binding in the knee joints of RA patients. Methods  Data from six patients with RA were analysed. Dynamic PET scans were acquired in 3-D mode following (R)-[¹¹C]PK11195 injection. During scanning arterial radioactivity concentrations were measured to determine the plasma (R)-[¹¹C]PK11195 concentrations. Data were analysed using irreversible and reversible one-tissue and two-tissue compartment models and input functions with various types of metabolite correction. Model preferences according to the Akaike information criterion (AIC) and correlations between measures were evaluated. Correlations between distribution volume (V_d) and standardized uptake values (SUV) were evaluated. Results  AIC indicated optimal performance for a one-tissue reversible compartment model including blood volume. High correlations were observed between V_d obtained using different input functions (R ²=0.80–1.00) and between V_d obtained with one- and two-tissue reversible compartment models (R ²=0.75–0.94). A high correlation was observed between optimal V_d and SUV after injection (R ²=0.73). Conclusion  (R)-[¹¹C]PK11195 kinetics in the knee were best described by a reversible single-tissue compartment model including blood volume. Applying metabolite corrections did not increase sensitivity. Due to the high correlation with V_d, SUV is a practical alternative for clinical use. Financial support: There were no sources of financial support other than the VU University Medical Centre. The authors had full control of all primary data and agree to allow EJNM to review their data if requested.     

The relationship between the dopaminergic system and depressive symptoms in cervical dystonia

Purpose

Cervical dystonia (CD) is associated with tremor/jerks (50%) and psychiatric complaints (17–70%). The dopaminergic system has been implicated in the pathophysiology of CD in animal and imaging studies. Dopamine may be related to the motor as well as non-motor symptoms of CD. CD is associated with reduced striatal dopamine D_2/3 (D2/3) receptor and increased dopamine transporter (DAT) binding. There are differences in the dopamine system between CD patients with and without jerks/tremor and psychiatric symptoms.

Methods

Patients with CD and healthy controls underwent neurological and psychiatric examinations. Striatal DAT and D2/3 receptor binding were assessed using [¹²³I]FP-CIT and [¹²³I]IBZM SPECT, respectively. The ratio of specific striatal to non-specific binding (binding potential; BP_ND) was the outcome measure.

Results

Twenty-seven patients with CD and 15 matched controls were included. Nineteen percent of patients fulfilled the criteria for a depression. Striatal DAT BP_ND was significantly lower in depressed versus non-depressed CD patients. Higher DAT BP_ND correlated significantly with higher scores on the Unified Myoclonus Rating Scale (UMRS). The striatal D2/3 receptor BP_ND in CD patients showed a trend towards lower binding compared to controls. The D2/3 BP_ND was significantly lower in depressed versus non-depressed CD patients. A significant correlation between DAT and D2/3R BP_ND was found in both in patients and controls.

Conclusions

Alterations of striatal DAT and D2/3 receptor binding in CD patients are related mainly to depression. DAT BP_ND correlates significantly with scores on the UMRS, suggesting a role for dopamine in the pathophysiology of tremor/jerks in CD.

     

Quantification of dopamine transporter density with [18F]FECNT PET in healthy humans

IntroductionFluorine-18 labeled 2β-carbomethoxy-3β-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane ([¹⁸ F]FECNT) binds reversibly to the dopamine transporter (DAT) with high selectivity. [¹⁸ F]FECNT has been used extensively in the quantification of DAT occupancy in non-human primate brain and can distinguish between Parkinson's and healthy controls in humans. The purpose of this work was to develop a compartment model to characterize the kinetics of [¹⁸ F]FECNT for quantification of DAT density in healthy human brain.MethodsTwelve healthy volunteers underwent 180 min dynamic [¹⁸ F]FECNT PET imaging including sampling of arterial blood. Regional time-activity curves were extracted from the caudate, putamen and midbrain including a reference region placed in the cerebellum. Binding potential, BP_ND, was calculated for all regions using kinetic parameters estimated from compartmental and Logan graphical model fits to the time-activity data. Simulations were performed to determine whether the compartment model could reliably fit time-activity data over a range of BP_ND values.ResultsThe kinetics of [¹⁸ F]FECNT were well-described by the reversible 2-tissue arterial input and full reference tissue compartment models. Calculated binding potentials in the caudate, putamen and midbrain were in good agreement between the arterial input model, reference tissue model and the Logan graphical model. The distribution volume in the cerebellum did not reach a plateau over the duration of the study, which may be a result of non-specific binding in the cerebellum. Simulations that included non-specific binding show that the reference and arterial input models are able to estimate BP_ND for DAT densities well below that observed in normal volunteers.ConclusionThe kinetics of [¹⁸ F]FECNT in human brain are well-described by arterial input and reference tissue compartment models. Measured and simulated data show that BP_ND calculated with reference tissue model is proportional to BP_ND calculated from the arterial input model.     

Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers

Purpose

Positron emission tomography (PET) imaging of serotonin 2A (5-HT_2A) receptors with agonist tracers holds promise for the selective labelling of 5-HT_2A receptors in their high-affinity state. We have previously validated [¹¹C]Cimbi-5 and found that it is a 5-HT_2A receptor agonist PET tracer. In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [¹¹C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT_2A receptor agonist PET tracers in the pig brain.

Methods

Each radiotracer was injected intravenously into anaesthetized Danish Landrace pigs, and the pigs were subsequently scanned for 90?min in a high-resolution research tomography scanner. To evaluate 5-HT_2A receptor binding, cortical nondisplaceable binding potentials (BP_ND) were calculated using the simplified reference tissue model with the cerebellum as a reference region.

Results

After intravenous injection, all compounds entered the brain and distributed preferentially into the cortical areas, in accordance with the known 5-HT_2A receptor distribution. The largest target-to-background binding ratio was found for [¹¹C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [¹¹C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT_2A receptor selectivity in vivo. [¹¹C]Cimbi-82 and [¹¹C]Cimbi-21 showed lower cortical BP_ND, while [¹¹C]Cimbi-27, [¹¹C]Cimbi-29, [¹¹C]Cimbi-31 and [¹¹C]Cimbi-88 gave rise to cortical BP_ND similar to that of [¹¹C]Cimbi-5.

Conclusion

[¹¹C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT_2A receptor agonist binding in the living human brain with PET.