Optimal Acquisition Time Window and Simplified Quantification of Dopamine Transporter Availability Using ¹⁸F-FE-PE2I in Healthy Controls and Parkinson Disease Patients

Abstract

nortropane ( 18 F-FE-PE2I) is a newly developed dopamine transporter (DAT) PET radioligand. Full quantification methods rely on dynamic acquisition of 18 F-FE-PE2I, but in a clinical setting a simplified protocol is preferable. The aims of this study were to identify the optimal acquisition time window for 18 F-FE-PE2I and to validate the specific binding ratio (SBR) as a simplified quantification method. Methods: Ten Parkinson disease (PD) patients and 10 controls were included. Ninety-three-min dynamic PET measurements with 18 F-FE-PE2I were conducted using the high-resolution research tomograph (HRRT). The dynamic measurement was also smoothed to the resolution of a clinical PET system (HR). Regions of interest for the caudate, putamen, ventral striatum, substantia nigra (SN), and cerebellum were manually drawn on coregistered MR images. The outcome measure was the SBR, and the gold standard was the binding potential obtained with wavelet-aided parametric imaging (WAPI BP ND ). The cerebellum was used as a reference region. In a preliminary analysis, SBR was computed for 8 time windows (SBR dyn ). Linear regression analysis and Bland-Altman plots were used to select the optimal acquisition time window. An average image from the selected time window was created, from which new SBR values (SBR calculated on the average image on the HRRT and SBR calculated on the average image on the simulated HR images) were calculated and compared with WAPI BP ND . The effect size was calculated. Results: SBR dyn values for the time window between 16.5 and 42 min correlated best with WAPI BP ND (r 2 5 0.98, P , 0.001). Significant correlations (P , 0.001) were observed between SBR HR and WAPI-BP ND (r 2 5 0.95 in controls and 0.97 in PD patients). In the striatum, SBR HR values were 37% lower than BP ND in controls, 29% in PD patients, whereas in the SN the underestimation was 22% in controls and 15% in PD patients. Similar effect sizes for BP ND and SBR HR were found in the caudate (0.6), putamen (1.7 and 1.4), ventral striatum (0.7), and SN (0.5 and 0.4). Conclusion: A single 18 F-FE-PE2I acquisition between 16.5 and 42 min provides the best outcome measure for simplified DAT quantification. Despite underestimation of the BP ND , the SBR can be used in a clinical setting as a valid quantification method for DAT using 18 F-FE-PE2I, because it provides differentiation similar to BP ND between controls and PD patients. The dopaminergic system has a crucial role in the pathogenesis of several psychiatric and neurodegenerative diseases (1-6) and has been the focus of research for decades. The link between dopaminergic degeneration and the pathophysiology of motor symptoms in Parkinson disease (PD) has been known for more than a century (7), and despite this acquired knowledge the dopaminergic system is still an active field of research.The dopamine transporter (DAT), a presynaptic membrane protein responsible for dopamine reuptake, plays a key role in regulating the intensity and duration of the dopaminergic neurotransmission (8,...

Whole-Body Biodistribution and Dosimetry of the Dopamine Transporter Radioligand 18F-FE-PE2I in Human Subjects

“…The first study, including 10 Parkinson disease patients and 10 age-and sex-matched control subjects, demonstrated the ability of 18 F-FE-PE2I to quantify the nigrostriatal DAT loss in Parkinson disease (9). Findings from further studies supported the use of 18 F-FE-PE2I as a diagnostic tool for the evaluation of parkinsonian patients in the clinical setting (9)(10)(11).…”

“…18 F-(E)-N-(3-iodoprop-2-enyl)-2b-carbofluoroethoxy-3b-(49methyl-phenyl) nortropane ( 18 F-FE-PE2I) is a recently developed radioligand that shows suitable characteristics for a DAT imaging tool both in nonhuman primates (NHPs) and in human subjects. The fast washout from the brain and the favorable metabolism make 18 F-FE-PE2I superior to other related PET radioligands (e.g., 11 C-PE2I and 18 F-FECNT) for DAT quantification (5)(6)(7). In addition, the relatively high specific-to-nondisplaceable binding ratio of 18 F-FE-PE2I permits quantification of the DAT also in extrastriatal regions, such as the substantia nigra, where the cell bodies of the dopaminergic neurons are located.…”

“…This permitted the first-in-humans (to our knowledge) validation of 18 F-FE-PE2I (10). The estimates of the effective dose based on biokinetic data from NHPs are usually considered predictive of the actual dose to human subjects, although some discrepancies can be expected (11). Therefore, a full evaluation of whole-body distribution and dosimetry in human subjects will be warranted before widespread application of the PET imaging agent.…”

Neuroimaging in pre-motor Parkinson's disease

“…The presynaptic dopamine transporter (DAT) can be targeted with compounds such as 18 F-FP-CIT, 11 C-methylphenidate ( 11 C-MP) or 18 F-FE-PE2I (Sonni et al, 2016). The intracellular vesicular monoamine transporter (VMAT2) is responsible for re-packaging dopamine into vesicles, and is commonly labelled with 11 C-dihydrotetrabenazine ( 11 C-DTBZ) or 18 F-fluoropropyl-dihydrotetrabenazine ( 18 F-FP-DTBZ).…”

Reliability of Dopamine Transporter PET Measurements with [18F]FE-PE2I in patients with Parkinson´s Disease

“…[ 18 F]FE-PE2I, developed in 2009 [1,2], has, through several validity studies, proven to be a valuable positron emission tomography (PET) radioligand for dopamine transporter (DAT) imaging [1][2][3][4][5][6][7][8]. A clinical PET study with [ 18 F]FE-PE2I in 20 patients with early-stage PD showed an in vivo striato-nigral gradient of DATloss [9], in agreement with post-mortem studies in patients, and animal model studies [10,11].…”