PE2I: A Radiopharmaceutical for In vivo Exploration of the Dopamine Transporter

Abstract

The membrane dopamine transporter (DAT) has a pivotal role in the regulation of dopamine (DA) neurotransmission involved in a number of physiological functions and brain disorders. Molecular imaging techniques, such as positron emission tomography (PET) and single photon emission computerized tomography (SPECT), are relevant tools to explore the DAT, and we developed the cocaine derivative N-(3-iodopro-2E-enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl) nortropane (PE2I) that has proved to be a very potent radiopharmaceutical to image the DAT by these techniques. Several methods are available to obtain PE2I labeled with iodine-123 or -125, carbon-11 and tritium. The pharmacological properties of PE2I have demonstrated that it has good affinity for the DAT (4 nM) and is one of the most selective DAT ligands. [(125)I]PE2I characterized postmortem in human brains has revealed very intense and selective binding in the basal ganglia. Ex vivo autoradiography in rats has shown that high level of [(125)I]PE2I accumulates in the striatum and also in the substantia nigra and ventral tegmental area. [(125)I]PE2I accumulation in the rat striatum is rapid, high, and selective, providing a maximum striatum/cerebellum ratio of 10 during the first 30 min post injection. Using SPECT or PET, rapid, high, and selective accumulation of PE2I was found in the caudate nucleus and putamen in monkeys, whereas rapid wash out from the cerebellum was observed. In vivo investigations in healthy humans have demonstrated that PE2I has high striatal uptake, low nonspecific binding, low radiation exposure, and a fairly short scanning time. A number of findings in various animal models of Parkinson's disease in rats and monkeys have demonstrated the high efficacy of PE2I for detection of reduction in the density of DAT, thus showing the potential value of PE2I for early diagnosis and evaluation of treatment of this disease. The excellent properties of PE2I are basis for the development of new DAT tracers for use in future PET explorations using fluor-18.

Modeling Considerations for In Vivo Quantification of the Dopamine Transporter using [11C]PE2I and Positron Emission Tomography

“…In competition studies, PE2I showed high affinity for DAT in vitro (K i = 17 nM) with significantly lower binding affinity for serotonin or norepinephrine transporters (Emond et al ., 2008). In vitro saturation studies have also validated PE2I’s high DAT affinity, resulting in a measured (Na+ dependent) K d of 3.9 nM in 120 mmol/L of NaCl (Emond et al ., 2008). However, DAT measurements using PE2I have shown great variability (Jucaite et al ., 2006; Leroy et al ., 2007).…”

The Story of the Dopamine Transporter PET Tracer LBT-999: From Conception to Clinical Use

“…Among them, the N-(3-iodopro-2 E -enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane (PE2I) is structurally characterized by the presence of a methyl group on the phenyl ring of the β-CIT structure instead of an iodine, and a 3-iodopro-2E-enyl group at the tropane nitrogen instead of a methyl carried by β-CIT (18). These chemical modifications have led to a significant improvement in the pharmacological profile of this ligand (19, 20), showing a high selectivity for the DAT toward the serotonin transporter (SERT). The high affinity and selectivity made PE2I a highly potent tracer to image the DAT in vivo either by SPECT when labeled with 123 I and by PET when labeled with 11 C. In this context, [ 123 I]PE2I demonstrated its usefulness for the differential diagnosis between patients suffering from PD and atypical parkinsonian syndromes without degeneration of striatal dopaminergic nerve endings (21).…”

An Immunohistochemical Analysis on The Human Cerebellar Dopaminergic System

“…In the postmortem human cerebellum has been detected signi cant levels of dopamine (DA), homovanillic acid (HVA), the most catecholamine metabolite [8][9][10], tyrosine hydroxylase (TH), the rst enzyme involved in catecholamine biosynthesis, dopamine transporter (DAT), the membrane transporter involved in DA reuptake [11]. Positron emission tomography (PET) studies in monkey cerebellum and autoradiographic evaluations in human postmortem cerebellum has been detected the presence of selective dopamine transporter ligands (DAT-Ls) [12][13][14]. Moreover, in biochemical analysis has been revealed in rat and monkey cerebellum high levels of DA in the vermis lobules VII, VIII, IX, X, in the fastigial and dentate nuclei [11,[15][16][17].…”