Radiotracer For Use Research Articles

Pilot imaging of the colony stimulating factor 1 receptor in the brains of virally-suppressed individuals with HIV.

Neuroimmune activation is a putative driver of cognitive impairment in people with HIV (PWH), even in the age of modern antiretroviral therapy. Nevertheless, imaging of the microglial marker, the 18 kDa translocator protein (TSPO), with positron emission tomography (PET) in treated PWH has yielded inconclusive findings. One potential reason for the varied TSPO results is a lack of cell-type specificity of the TSPO target. [ 11 C]CPPC, 5-cyano- N -(4-(4-[ 11 C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl) furan-2-carboxaminde, is a radiotracer for use with PET to image the colony stimulating factor 1 receptor (CSF1R). The CSF1R is expressed on microglia and central nervous system macrophages, with little expression on other cell types. We used [ 11 C]CPPC PET in virally-suppressed- (VS)-PWH and HIV-uninfected individuals to estimate the effect sizes of higher CSF1R in the brains of VS-PWH. Sixteen VS-PWH and 15 HIV-uninfected individuals completed [ 11 C]CPPC PET. [ 11 C]CPPC binding (V T ) in nine regions was estimated using a one-tissue compartmental model with a metabolite-corrected arterial input function, and compared between groups. Regional [ 11 C]CPPC V T did not significantly differ between groups after age- and sex- adjustment [unstandardized beta coefficient ( B ) = 1.84, standard error (SE) = 1.18, P = 0.13]. The effect size was moderate [Cohen's d = 0.56, 95% confidence interval (CI) -0.16, 1.28), with strongest trend of higher V T in VS-PWH in striatum and parietal cortex (each P = 0.04; Cohen's d = 0.71 and 0.72, respectively). A group difference in [ 11 C]CPPC V T was not observed between VS-PWH and HIV-uninfected individuals in this pilot, although the observed effect sizes suggest the study was underpowered to detect regional group differences in binding.

Broad-scope Syntheses of [11 C/18 F]Trifluoromethylarenes from Aryl(mesityl)iodonium Salts.

Efficient methods for labeling aryl trifluoromethyl groups to provide novel radiotracers for use in biomedical research with positron emission tomography (PET) are keenly sought. We report a broad-scope method for labeling trifluoromethylarenes with either carbon-11 (t1/2 =20.4 min) or fluorine-18 (t1/2 =109.8 min) from readily accessible aryl(mesityl)iodonium salts. In this method, the aryl(mesityl)iodonium salt is treated rapidly with no-carrier-added [11 C]CuCF3 or [18 F]CuCF3 . The mesityl group acts as a spectator allowing radiolabeled trifluoromethylarenes to be obtained with very high chemoselectivity. Radiochemical yields from aryl(mesityl)iodonium salts bearing either electron-donating or electron-withdrawing groups at meta- or para- position are good to excellent (67-96 %). Ortho-substituted and otherwise sterically hindered trifluoromethylarenes still give good yields (15-34 %). Substituted heteroaryl(mesityl)iodonium salts are also viable substrates. The broad scope of this method was further exemplified by labeling a previously inaccessible target, [11 C]p-trifluoromethylphenyl boronic acid, as a potentially useful labeling synthon. In addition, fluoxetine, leflunomide, and 3-trifluoromethyl-4-aminopyridine, as examples of small drug-like molecules and candidate PET radioligands, were successfully labeled in high yields (69-81 %).

A new automated and putatively versatile synthesis of the PSMA-ligand derivative [18F]DCFPyL using the FASTlabTM synthesizer

BackgroundNoninvasive molecular imaging using peptides and biomolecules labelled with positron emitters has become important for detection of cancer and other diseases with PET (positron emission tomography). The positron emitting radionuclide fluorine-18 is widely available in high yield from cyclotrons and has favorable decay (t1/2 109.7 min) and imaging properties. 18F-Labelling of biomolecules and peptides for use as radiotracers is customarily achieved in a two-step approach, which can be challenging to automate. 6-[18F]Fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester ([18F]F-Py-TFP) is a versatile 18F-prosthetic group for this purpose, which can be rapidly be produced in an one-step approach on solid support. This work details an automated procedure on the cassette-based GE FASTlab™ platform for the labeling of a peptidomimetic, exemplified by the case of using the Glu-CO-Lys motif to produce [18F]DCFPyL, a ligand targeting the prostate specific membrane antigen (PSMA).ResultsFrom fluorine-18 delivery a fully automated two-step radiosynthesis of [18F]DCFPyL was completed in 56 min with an overall end of synthesis yield as high as 37% using solid phase extraction (SPE) purification on the GE FASTlab™ platform.ConclusionsPutatively, this radiolabeling methodology is inherently amenable to automation with a diverse set of synthesis modules, and it should generalize for production of a broad spectrum of biomolecule-based radiotracers for use in PET imaging.

Translational Development Strategies for TAK-063, a Phosphodiesterase 10A Inhibitor.

BackgroundTAK-063 is an inhibitor of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the striatum. PDE10A hydrolyzes both cyclic adenosine monophosphate and cyclic guanosine monophosphate and modulates dopamine signaling downstream of receptor activation in both direct and indirect pathways of the striatum. TAK-063 exhibited antipsychotic-like effects in animal models; however, the translatability of these models to the clinical manifestations of schizophrenia and the meaningfulness for new targets such as PDE10A has not been established.MethodsThe TAK-063 phase 1 program included a comprehensive translational development strategy with the main objective of determining whether the antipsychotic-like pharmacodynamic effects seen in nonclinical models would translate to human subjects. To evaluate this objective, we conducted a single-rising dose study (84 healthy subjects), a positron emission tomography (PET) study (12 healthy subjects), a functional magnetic resonance imaging blood oxygen level-dependent (BOLD) study (27 healthy subjects), and a multiple-rising dose study that included people with schizophrenia (30 healthy Japanese subjects and 47 subjects with stable schizophrenia). In addition, assessments of cognition and electroencephalography (27 healthy subjects and 47 subjects with stable schizophrenia) were included.ResultsPDE10A engagement by TAK-063 was verified with a novel PET radiotracer for use in primates and humans. TAK-063 showed favorable pharmacokinetic and safety profiles in humans, and TAK-063 reduced ketamine-induced changes in electroencephalography and BOLD signaling in animal models and healthy human subjects. In addition, analogous effects on cognition were observed in animal models and human subjects.ConclusionsOverall, the phase 1 results showed some consistent evidence of antipsychotic activity. This translational strategy may be valuable for the future development of novel therapeutic approaches, even when relevant nonclinical models are not available.

Early-phase [18F]PI-2620 tau-PET imaging as a surrogate marker of neuronal injury

PurposeSecond-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several β-amyloid and first-generation tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer [18F]PI-2620 as a potential substitute for [18F]fluorodeoxyglucose ([18F]FDG).MethodsTwenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson’s disease, multi-system atrophy, Parkinson's disease, frontotemporal dementia) and received a dynamic [18F]PI-2620 tau-PET (0–60 min p.i.) and static [18F]FDG-PET (30–50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R1) of [18F]PI-2620-PET were correlated with corresponding quantification of [18F]FDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase [18F]PI-2620 tau-PET and [18F]FDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers.ResultsHighest agreement with [18F]FDG-PET quantification was reached for [18F]PI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest R = 0.69) and cerebellar scaling (lowest R = 0.63). Correlation coefficients (summed 0.5–2.5 min SUVr & R1) displayed strong agreement in all cortical target regions for global mean (RSUVr 0.76, RR1 = 0.77) and cerebellar normalization (RSUVr 0.68, RR1 = 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and [18F]FDG-PET. There were no relevant differences between more and less experienced readers.ConclusionEarly-phase imaging of [18F]PI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional [18F]FDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.

A Longitudinal Evaluation of a Radiotracer for Use in Tau Tracking

A Longitudinal Evaluation of a Radiotracer for Use in Tau Tracking

Piramal Imaging.

Piramal Imaging, a division of Piramal Enterprises Ltd, is a global radiopharmaceutical company that is actively developing novel PET radiotracers for use in molecular imaging. The company focuses on developing innovative products that improve early detection and characterization of chronic and life-threatening diseases, leading to better therapeutic outcomes and improved quality of life.

Preparation of the metabotropic glutamate receptor 5 (mGluR5) PET tracer [18F]FPEB for human use: An automated radiosynthesis and a novel one-pot synthesis of its radiolabeling precursor

The radiotracer 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile, or [18F]FPEB, is a promising PET imaging agent for the metabotropic glutamate subtype 5 receptor (mGluR5). In an effort to develop a routine production method of this radiotracer for use in clinical research we adapted its radiosynthesis to an automated chemistry module. In the meanwhile, we also developed a simplified “one-pot” method for the preparation of the nitrobenzonitrile radiolabeling precursor for [18F]FPEB and its reference standard to replace the existing multi-step synthetic approach.

Estimating endogenous dopamine levels at D2 and D3 receptors in humans using the agonist radiotracer [(11)C]-(+)-PHNO.

Using positron emission tomography (PET) and an acute dopamine depletion challenge it is possible to estimate endogenous dopamine levels occupying dopamine D2/3 receptors (D2/3R) in humans in vivo. Our group has developed [(11)C]-(+)-PHNO, the first agonist radiotracer with preferential in vivo affinity for D3R. Thus, the use of [(11)C]-(+)-PHNO offers the novel possibility of (i) estimating in vivo endogenous dopamine levels at D2/3R using an agonist radiotracer, and (ii) estimating endogenous dopamine levels at D3R in extrastriatal regions such as the substantia nigra, hypothalamus, and ventral pallidum. Ten healthy participants underwent a [(11)C]-(+)-PHNO PET scan under baseline conditions and another under acute endogenous dopamine depletion achieved via oral administration of alpha-methyl-para-tyrosine (64 mg/kg). [(11)C]-(+)-PHNO binding was sensitive to acute dopamine depletion, allowing in vivo estimates of endogenous dopamine in D2R-rich regions (caudate and putamen), mixed D2/3R-rich regions (ventral striatum and globus pallidus), and extrastriatal D3R-rich regions (hypothalamus and ventral pallidum). Dopamine depletion decreased self-reported vigor, which was correlated with the reduction in dopamine levels in the globus pallidus. [(11)C]-(+)-PHNO is a suitable radiotracer for use in estimating endogenous dopamine levels at D2R and D3R in neuropsychiatric populations.

Single step 18F-labeling of dimeric cycloRGD for functional PET imaging of tumors in mice

Arylboronates afford rapid aqueous (18)F-labeling via the creation of a highly polar (18)F-aryltrifluoroborate anion ((18)F-ArBF3(-)). Radiosynthesis of an (18)F-ArBF3(-) can be successfully applied to a clinically relevant peptide. To test this hypothesis, we labeled dimeric-cylcoRGD, [c(RGDfK)]2E because a) it is molecularly complex and provides a challenging substrate to test the application of this technique, and b) [c(RGDfK)]2E has already been labeled via several (18)F-labeling methods which provide for a preliminary comparison. To validate this labeling method in the context of a complex and clinically relevant tracer to show tumor-specific uptake ex vivo with representative PET images in vivo. An arylborimidine was conjugated to [c(RGDfK)]2E to give the precursor [c(RGDfK)]2E-ArB(dan), which was aliquoted and stored at -20 °C. Aliquots of 10 or 25 nmol, containing only micrograms of precursor, were labeled using relatively low levels of (18)F-activity. Following purification eight mice (pre-blocked/unblocked) with U87M xenograft tumors were injected with [c(RGDfK)]2E-(18)F-ArBF3(-) (n = 4) for ex vivo tissue dissection. Two sets of mice (pre-blocked/unblocked) were also imaged with PET-CT (n = 2). The [c(RGDfK)]2E-ArB(dan) is converted within 15 min to [c(RGDfK)]2E-(18)F-ArBF3(-) in isolated radiochemical yields of ~10% (n = 3) at a minimum effective specific activity of 0.3 Ci/μmol. Biodistribution shows rapid clearance to the bladder via the kidney resulting in high tumor-to-blood and tumor-to-muscle ratios of >9 and >6 respectively while pre-blocking with [c(RGDfK)]2E showed high tumor specificity. PET imaging showed good contrast between tumor and non-target tissues confirming the biodistribution data. An arylborimidine-RGD peptide is rapidly (18)F-labeled in one step, in good yield, at useful specific activity. Biodistribution studies with blocking controls show tumor specificity, which is corroborated by PET images. Advances in Knowledge and Implications for patient Care: Despite many antecedent examples of labeled RGD tracers, this work is the first to show direct aqueous labeling of bisRGD with an (18)F-ArBF3(-). Labeling occurs in near record rapidity (45 min) at useful effective specific activities and competitive yields for high contrast tumor specific images. As bisRGD has been imaged in humans with several prosthetics, this work suggests potential clinical applications of tracers appended with an (18)F-ArBF3(-). More generally, the ability to label a molecularly complex tracer suggests that this method could be useful to label many other peptides. Furthermore, these results portend the development of kits that use only microgram quantities of lyophilized precursor for on demand labeling. The ability to perform one-step aqueous labeling in under an hour to provide tracers with high T:NT ratios has important implications for developing radiotracers for use in fundamental research and in preclinical tracer studies.

α-synuclein Imaging: A Critical Need for Parkinson's Disease Research

The development of an α-synuclein imaging agent could be transformative for Parkinson's disease research and drug development. The ability to image α-synuclein in the brain would enable tracking of the degree and location of pathology over time and monitoring of therapies aimed at reducing α-synuclein levels. The Michael J. Fox Foundation has assembled a consortium of researchers to develop an α-synuclein radiotracer for use in positron emission tomography (PET) imaging studies. While this poses a number of challenges they should not be insurmountable and lessons learned from the development of tau radiotracers should provide valuable insights.

Pharmacokinetic and toxicological evaluation of multi-functional thiol-6-fluoro-6-deoxy-d-glucose gold nanoparticles in vivo

We synthesized a novel, multi-functional, radiosensitizing agent by covalently linking 6-fluoro-6-deoxy-d-glucose (6-FDG) to gold nanoparticles (6-FDG–GNPs) via a thiol functional group. We then assessed the bio-distribution and pharmacokinetic properties of 6-FDG–GNPs in vivo using a murine model. At 2 h, following intravenous injection of 6-FDG–GNPs into the murine model, approximately 30% of the 6-FDG–GNPs were distributed to three major organs: the liver, the spleen and the kidney. PEGylation of the 6-FDG–GNPs was found to significantly improve the bio-distribution of 6-FDG–GNPs by avoiding unintentional uptake into these organs, while simultaneously doubling the cellular uptake of GNPs in implanted breast MCF-7 adenocarcinoma. When combined with radiation, PEG–6-FDG–GNPs were found to increase the apoptosis of the MCF-7 breast adenocarinoma cells by radiation both in vitro and in vivo. Pharmacokinetic data indicate that GNPs reach their maximal concentrations at a time window of two to four hours post-injection, during which optimal radiation efficiency can be achieved. PEG–6-FDG–GNPs are thus novel nanoparticles that preferentially accumulate in targeted cancer cells where they act as potent radiosensitizing agents. Future research will aim to substitute the 18F atom into the 6-FDG molecule so that the PEG–6-FDG–GNPs can also function as radiotracers for use in positron emission tomography scanning to aid cancer diagnosis and image guided radiation therapy planning.

Development of Tyrosine-Based RadiotracerTc99m-N4-Tyrosine for Breast Cancer Imaging

The purpose of this study was to develop an efficient way to synthesize 99mTc-O-[3-(1,4,8,11-tetraazabicyclohexadecane)-propyl]-tyrosine (99mTc-N4-Tyrosine), a novel amino acid-based radiotracer, and evaluate its potential in breast cancer gamma imaging. Precursor N4-Tyrosine was synthesized using a 5-step procedure, and its total synthesis yield was 38%. It was successfully labeled with 99mTc with high radiochemical purity (>95%). Cellular uptake of 99mTc-N4-Tyrosine was much higher than that of 99mTc-N4 and the clinical gold standard 18F-2-deoxy-2-fluoro-glucose (18F-FDG) in rat breast tumor cells in vitro. Tissue uptake and dosimetry estimation in normal rats revealed that 99mTc-N4-Tyrosine could be safely administered to humans. Evaluation in breast tumor-bearing rats showed that although 99mTc-N4-Tyrosine appeared to be inferior to 18F-FDG in distinguishing breast tumor tissue from chemical-induced inflammatory tissue, it had high tumor-to-muscle uptake ratios and could detect breast tumors clearly by planar scintigraphic imaging. 99mTc-N4-Tyrosine could thus be a useful radiotracer for use in breast tumor diagnostic imaging.

SPECT Imaging Agents for Detecting Cerebral β-Amyloid Plaques

The development of radiotracers for use in vivo to image β-amyloid (Aβ) plaques in cases of Alzheimer's disease (AD) is an important, active area of research. The presence of Aβ aggregates in the brain is generally accepted as a hallmark of AD. Since the only definitive diagnosis of AD is by postmortem staining of affected brain tissue, the development of techniques which enable one to image Aβ plaques in vivo has been strongly desired. Furthermore, the quantitative evaluation of Aβ plaques in the brain could facilitate evaluation of the efficacy of antiamyloid therapies currently under development. This paper reviews the current situation in the development of agents for SPECT-based imaging of Aβ plaques in Alzheimer's brains.

Preparation and preliminary bioevaluation of 99mTc(CO)3-11β-progesterone derivative prepared via click chemistry route

Progesterone receptors (PRs) overexpressed in breast cancers serve as potential targets for developing radiotracers for use in nuclear medicine. Hence, suitably derivatized progesterone can be envisaged as a potential vector for targeting overexpression of receptors in breast cancer. In the present article, we report the preparation of a (99m)Tc(CO)(3)-progesterone triazole using the Cu(I)-catalyzed novel click chemistry route. Preliminary evaluation of the radiolabeled derivative has been carried out in binding studies with MCF 7 cell lines. 11-Hydroxyprogesterone has been synthetically derivatized to 11-azidoprogesterone. Subsequently, the cycloaddition reaction between progesterone azide and propargyl glycine was carried out to prepare 1,4-bifunctionalized progesterone triazole analogue. The clicked progesterone triazole derivative was radiolabeled with (99m)Tc and characterized by HPLC. The chemical characterization of (99m)Tc(CO)(3)-progesterone triazole has been carried out by preparing its corresponding rhenium complex using the [NEt(4)](2)[Re(CO)(3)Br(3)] precursor. While in vitro studies were carried out in MCF7 cell lines, in vivo distribution studies were performed in female Swiss mice. The radiolabeled complex could be prepared in >95% radiochemical yield as determined by HPLC. In vitro studies of (99m)Tc(CO)(3)-progesterone complex in MCF7 cell lines overexpressing receptors for breast cancer showed binding up to 30%. In vivo distribution studies in female Swiss mice have shown uterine uptake of 0.41 (0.06) % ID/g at 3 h postinjection (pi) and retention therein till 24 h pi. The present study demonstrates a novel and facile route for preparation of (99m)Tc-labeled progesterone complex using click chemistry. This strategy can be further extended towards preparation of radiolabeled complexes of other steroidal derivatives.

Comparative evaluation of various solid phases for the development of coated tube assays for the estimation of progesterone in human serum, bovine serum and bovine milk

Immobilization of progesterone antibody using three polystyrene surfaces and two progesterone radiotracers for use in the development of a coated tube assay for the evaluation of progesterone levels in human serum, bovine serum and bovine milk was studied. The selection of the solid phase and the tracers were based on the maximum binding, non-specific binding, sensitivity and percentage recovery. Amongst the polystyrene tubes studied, streptavidin coated tubes showed the acceptable assay features such as low non-specific binding (0.5–1.0%), adequate sensitivity (0.13–0.16 ng/ml) and recovery (85–115%) for all the three sample matrices, human serum, bovine serum and bovine milk.

In vivo amyloid imaging with the new radiotracer [N-Methyl-11C]2-(4'-(methylamino)phenyl)-benzothiazol (C-11-BTA-1) in Alzheimer's disease

Aims: Over the last years there has been great effort to develop novel in vivo amyloid-imaging radiotracers for use with positron emission tomography (PET) to allow noninvasive in vivo assessments of amyloid plaques. This might lead to a better understanding of amyloid deposition over the course of disease in Alzheimer's disease (AD), and might eventually provide a surrogate marker of potential antiamyloid therapies.

Use of cyclotrons in medicine

Cyclotrons are versatile ion-accelerating machines which find many applications in medicine. In this short review their use in hadron therapy is briefly discussed. Proton therapy is gaining significance because of its capability to treat deep-lying tumours. A strong area of application of cyclotrons involves the production of short-lived neutron deficient radiotracers for use in emission tomography, especially positron emission tomography. This fast and quantitative in vivo diagnostic technique is being increasingly used in neurology, cardiology and oncology. Besides routine patient care, considerable interdisciplinary work on development of new positron emitters is under way. A short account of those efforts is given. The use of cyclotrons in the production of radionuclides for internal radiotherapy is also briefly described.

11C-Fallypride: radiosynthesis and preliminary evaluation of a novel dopamine D2/D3 receptor PET radiotracer in non-human primate brain

Fallypride [benzamide, 5-(3-fluoropropyl)-2,3-dimethoxy-N-[(2S)-1-(2-propenyl)-2-pyrrolidinyl]methyl]-, CAS RN 166173-78-0] is a selective dopamine D2/D3 receptor antagonist. Carbon-11 labeled fallypride may serve as a radiotracer for use in biomedical imaging technique positron emission tomography (PET). The precursor, 5-(3-fluoropropyl)-2-hydroxy-3-methoxy-N-[(2S)-1-(2-propenyl)-2-pyrrolidinyl]methyl]benzamide was synthesized from 2-hydroxy-3-methoxy-5-(2-propenyl)benzoic acid, methyl ester in seven steps with approximately 10% overall chemical yield. Using this precursor 11C-fallypride was produced by radiolabeling with 11C-methyl iodide in 25–40% radiochemical yields with specific activities of 200–1000 Ci/mmol. PET imaging studies in nonhuman primates with 11C-fallypride showed radiotracer localization in dopaminergic brain regions such as caudate, putamen, thalamus and cortex. This regional localization of 11C-fallypride is similar to that observed previously for 18F-fallypride. The results suggest 11C-fallypride is a useful PET radiotracer for imaging dopamine D2/D3 receptors.

Protection of dopaminergic nigrostriatal afferents by GDNF delivered by microspheres in a rodent model of Parkinson's disease.

The use of glial cell line-derived neurotrophic factor (GDNF) appears to be a promising strategy to promote survival and function of the nigrostriatal dopaminergic pathway damaged in Parkinson's disease (PD). However, effective intracerebral administration is required for optimal therapeutic benefit and tools to evaluate such therapies must be developed. A rodent model of PD was therefore developed using striatal injection of 6-hydroxydopamine (6-OHDA) with simultaneous implantation of GDNF-delivering microspheres. The effects of GDNF released from microspheres were assessed by classical methods such as amphetamine-induced rotating behavior and tyrosine hydroxylase (TH) immunoreactivity, as well as by quantitative autoradiography using PE2I, a dopamine transporter (DAT) radiotracer, which is also suitable for SPET imaging in humans. 6-OHDA-lesioned animals that received microspheres without GDNF were used as controls. During the first 3 weeks after simultaneous lesion and implantation, the amphetamine-induced rotating behavior of GDNF-treated rats was improved compared to controls and an increase in TH expression (+26%) was measured in the striatum 6 weeks after lesion. In accordance with these results, an increase in striatal PE2I-labeled DAT density was obtained (+17%) after 3 and 6 weeks of treatment. In conclusion, this study demonstrates the neuroprotective action of GDNF delivered by microspheres and suggests that PE2I may be an appropriate radiotracer for use in SPET scintigraphy to follow up treatment of PD in humans.