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Purpose: To decipher the relevance of visual and semi-quantitative 6-fluoro-(18F)-L-DOPA (18F-DOPA) interpretation methods for the diagnostic of idiopathic Parkinson disease (IPD) in hybrid positron emission tomography (PET) and magnetic resonance imaging. Material and methods: A total of 110 consecutive patients (48 IPD and 62 controls) with 11 months of median clinical follow-up (reference standard) were included. A composite visual assessment from five independent nuclear imaging readers, together with striatal standard uptake value (SUV) to occipital SUV ratio, striatal gradients and putamen asymmetry-based semi-quantitative PET metrics automatically extracted used to train machine learning models to classify IPD versus controls. Using a ratio of 70/30 for training and testing sets, respectively, five classification models—k-NN, LogRegression, support vector machine, random forest and gradient boosting—were trained by using 100 times repeated nested cross-validation procedures. From the best model on average, the contribution of PET parameters was deciphered using the Shapley additive explanations method (SHAP). Cross-validated receiver operating characteristic curves (cv-ROC) of the most contributive PET parameters were finally estimated and compared. Results: The best machine learning model (k-NN) provided final cv-ROC of 0.81. According to SHAP analyses, visual PET metric was the most important contributor to the model overall performance, followed by the minimum between left and right striatal to occipital SUV ratio. The 10-time cv-ROC curves of visual, min SUVr or both showed quite similar performance (mean area under the ROC of 0.81, 0.81 and 0.79, respectively, for visual, min SUVr or both). Conclusion: Visual expert analysis remains the most relevant parameter to predict IPD diagnosis at 11 months of median clinical follow-up in 18F-FDOPA. The min SUV ratio appears interesting in the perspective of simple semi-automated diagnostic workflows. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Activated microglia/macrophages play a key role in the immunopathogenesis of MS and its corresponding animal models, experimental autoimmune encephalomyelitis (EAE). Microglia activation begins at early stages of the disease and is associated with elevated expression of the 18 kDa mitochondrial translocator protein (TSPO). Thus, positron emission tomography (PET) imaging of microglial activation using TSPO-specific radioligands could be valuable for monitoring disease-associated neuroinflammatory processes. EAE was induced in rats using a fragment of myelin basic protein, yielding acute clinical disease that reflects extensive spinal cord inflammation. Enhanced TSPO expression in spinal cords of EAE rats versus those of controls was confirmed by Western blot and immunohistochemistry. Biodistribution studies in control and EAE rats were performed using the TSPO radioligand [ 18F]DPA-714 [N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5- a]pyrimidin-3-yl)acetamide]. At 1 h after injection, almost fivefold higher levels of [ 18F]DPA-714 were measured in spinal cords of EAE rats versus controls. The specific binding of [ 18F]DPA-714 to TSPO in spinal cords was confirmed in competition studies, using unlabeled (R,S)-PK11195 [(R,S)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide)] or DPA-714 in excess. MicroPET studies affirm that this differential radioactivity uptake in spinal cords of EAE versus control rats could be detected and quantified. Using [ 18F]DPA-714, neuroinflammation in spinal cords of EAE-induced rats could be visualized by PET, offering a sensitive technique for monitoring neuroinflammatory lesions in the CNS and particularly in the spinal cord. In addition to current MRI protocols, this approach could provide molecular images of neuroinflammation for detection, monitoring, and research in MS. [ABSTRACT FROM AUTHOR]

Abstract. Longitudinal positron emission tomography (PET) studies of 6-[sup 18]F-L-dopa uptake in the striatum are used to assess the progression of Parkinson's disease or the survival of neuronal cells grafted in parkinsonian patients. These studies are performed over several years, and data analysis may suffer from the change from old tomographs to new machines with better sensitivity and spatial resolution. Furthermore, such studies on parkinsonian patients may be accomplished in either 2D or 3D acquisition mode. The aforementioned improvements offer great benefits for the study of neurodegenerative diseases, especially those affecting the striatum. However, direct comparison of data is not straightforward owing to variation in scanner characteristics. In this study, we assessed the feasibility of comparing the 6-[sup 18]F-L-dopa striatal uptake values (K[sub c]) measured in two groups of healthy subjects using two tomographs of different generations. We re-studied and compared acquisitions performed on 14 healthy subjects using 6-[sup 18]F-L-dopa. Half of these studies had been performed in 2D acquisition mode using an ECAT 953B. The other half had been performed in 3D acquisition mode using an ECAT EXACT HR+. Different reconstruction protocols were used and the K[sub c] values obtained were statistically compared. The results showed that lowering the transverse spatial resolution of images obtained with the scanner having the better spatial resolution, so that it more closely matched that of the other... [ABSTRACT FROM AUTHOR]

We have previously developed seven fluorinated analogues of A-836339 as new PET tracers for cannabinoid type 2 receptor (CB 2 R) imaging, among which ( Z )- N -(3-(2-(2-[ 18 F]fluoroethoxy)ethyl)-4,5-dimethylthiazol-2(3 H )-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide ([ 18 F]FC0324) displayed high affinity and selectivity for CB 2 R in healthy rats. In the present study, we have further evaluated the imaging and metabolic properties of [ 18 F]FC0324 in a rat model of human CB 2 R overexpression in the brain (AAV- h CB 2 ) and in non-human primates (NHPs). Autoradiography with AAV- h CB 2 rat brain sections exhibited a signal of [ 18 F]FC0324 8-fold higher in the ipsilateral region than in the contralateral region. Blocking with NE40, a CB 2 R-specific agonist, resulted in a 91% decrease in the radioactivity. PET experiments showed a signal 7-fold higher in the ipsilateral region, and the specificity of [ 18 F]FC0324 for h CB 2 R in vivo was confirmed by the 80% decrease after blocking with NE40. In NHPs, brain time-activity curves displayed a fast and homogeneous distribution followed by a rapid washout, in accordance with the low amount of CB 2 Rs in healthy brain. Whole-body PET-CT suggested a high and specific uptake of the radiotracer in the spleen, a CB 2 R-rich organ, and in the organs involved in metabolism and excretion, with a low bone uptake. In vitro metabolism with monkey liver microsomes (MLMs) led to the formation of six main hydroxylated metabolites of FC0324. Five of them were produced by human liver microsomes, being much less active than MLMs. In vivo, in NHPs, the main radiometabolite was likely to result from further oxidation of hydroxylated compounds, and parent [ 18 F]FC0324 accounted for 8 ± 3% of plasma radioactivity (at 120 min p.i.) with a low level of potential interfering radiometabolites. Furthermore, this metabolism should be significantly reduced in humans due to species differences. In conclusion, [ 18 F]FC0324 appears to be a promising candidate for further human studies with suitable kinetics, selectivity, and metabolic profile for CB 2 R PET imaging., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

18 F-DPA-714 is a second-generation tracer for PET imaging of the 18-kDa translocator protein (TSPO), a marker of neuroinflammation. Analysis and interpretation of TSPO PET are challenging, especially because of the basal expression of TSPO. The aim of this study was to evaluate a compartmental model that accounts for the effect of endothelial TSPO binding on the quantification of 18 F-DPA-714 PET scans from a cohort of healthy subjects. Methods: Fifteen healthy subjects (9 high-affinity binders and 6 mixed-affinity binders) underwent 18 F-DPA-714 PET scans with arterial blood sampling and metabolite analysis. The kinetic parameters were quantified using a 2-tissue compartmental model (2TC) as well as a 2TC with an extra, irreversible, compartment for endothelial binding (2TC-1K). These regional parameters and messenger RNA (mRNA) expression specific to endothelial cells were correlated with regional TSPO mRNA expression. Results: The 2TC-1K model was more appropriate than the 2TC for 81% of fits. The total volume of distribution was significantly reduced by 21% ± 12% across all regions with the 2TC-1K, compared with the 2TC. The endothelial binding parameter K b varied highly across brain regions. K b strongly and significantly correlated with all 3 probes extracted for TSPO mRNA expression ( r = 0.80, r = 0.79, and r = 0.90), but no correlation was seen with the other binding parameters from the 2TC-1K. For the 2TC, there was a lower but significant correlation between the volume of distribution and one of the TSPO mRNA probes ( r = 0.65). A strong, significant correlation was seen between mRNA for TSPO and genes specific to endothelial cells. Conclusion: Accounting for endothelial TSPO in the kinetic model improved the fit of PET data. The high correlation between K b and TSPO mRNA suggests that the 2TC-1K model reveals more biologic information about the regional density of TSPO than the 2TC. The correlation between TSPO and endothelial cell mRNA supports the relationship between the regional variation of K b and endothelial TSPO. These results can improve the estimation of binding parameter estimates from 18 F-DPA-714 PET, especially in diseases that induce vascular change., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Activated microglia/macrophages play a key role in the immunopathogenesis of MS and its corresponding animal models, experimental autoimmune encephalomyelitis (EAE). Microglia activation begins at early stages of the disease and is associated with elevated expression of the 18 kDa mitochondrial translocator protein (TSPO). Thus, positron emission tomography (PET) imaging of microglial activation using TSPO-specific radioligands could be valuable for monitoring disease-associated neuroinflammatory processes. EAE was induced in rats using a fragment of myelin basic protein, yielding acute clinical disease that reflects extensive spinal cord inflammation. Enhanced TSPO expression in spinal cords of EAE rats versus those of controls was confirmed by Western blot and immunohistochemistry. Biodistribution studies in control and EAE rats were performed using the TSPO radioligand [¹⁸F]DPA-714 [N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide]. At 1 h after injection, almost fivefold higher levels of [¹⁸F]DPA-714 were measured in spinal cords of EAE rats versus controls. The specific binding of [¹⁸F]DPA-714 to TSPO in spinal cords was confirmed in competition studies, using unlabeled (R,S)-PK11195 [(R,S)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide)] or DPA-714 in excess. MicroPET studies affirm that this differential radioactivity uptake in spinal cords of EAE versus control rats could be detected and quantified. Using [¹⁸F]DPA-714, neuroinflammation in spinal cords of EAE-induced rats could be visualized by PET, offering a sensitive technique for monitoring neuroinflammatory lesions in the CNS and particularly in the spinal cord. In addition to current MRI protocols, this approach could provide molecular images of neuroinflammation for detection, monitoring, and research in MS.