A novel 18F-labelled high affinity agent for PET imaging of the translocator protein

The translocator protein (TSPO) is an important target for imaging focal neuroinflammation in diseases such as brain cancer, stroke and neurodegeneration, but current tracers for non-invasive imaging of TSPO have important limitations. We present the synthesis and evaluation of a novel 3-fluoromethylquinoline-2-carboxamide, AB5186, which was prepared in eight steps using a one-pot two component indium(III)-catalysed reaction for the rapid and efficient assembly of the 4-phenylquinoline core. Biological assessment and the implementation of a physicochemical study showed AB5186 to have low nanomolar affinity for TSPO, as well as optimal plasma protein binding and membrane permeability properties. Generation of [18F]-AB5186 through 18F incorporation was achieved in good radiochemical yield and subsequent in vitro and ex vivo autoradiography revealed the ability of this compound to bind with specificity to TSPO in mouse glioblastoma xenografts. Initial positron emission tomography imaging of a glioma bearing mouse and a healthy baboon support the potential for [18F]-AB5186 use as a radiotracer for non-invasive TSPO imaging in vivo

Initial evaluation of [18F]F13714, a novel 5-HT1A receptor agonist in non-human primates

Présentation oraleInternational audienceAim. Brain serotonin 1A receptors (5-HT1A) exist in high- and low-affinity states. It is known that agonists bind preferentially to the high-affinity state of the receptors and therefore could provide a measure of the functional 5-HT1A receptors. Since all available fluorinated PET 5-HT1A radiopharmaceuticals are antagonists, it is of great interest to develop a fluorine-18 labelled agonist. [18F]F13714 is a novel ligand with high affinity (0.05 nM) for 5-HT1A receptors (J Nucl Med 2012; 53:969-976). Its nitro-precursor was synthesized and radiolabelled via a fluoronucleophilic substitution. Radiopharmacological evaluations included in vitro and ex vivo autoradiographies in rat brain and PETscans on rats and cats. With the Aim to prepare the transfer of this radiotracer in humans, we now report the first studies of [18F]F13714 in non-human primates. Materials and Methods. Four baseline PET studies, two blockade and one displacement studies with WAY-100635 (a 5-HT1A antagonist) were performed in two anaesthetized rhesus. Blood quantifications were done for each PET acquisition. Results and conclusion. The brain distribution of [18F]F13714 was consistent with 5-HT1A receptor distribution and confirmed data previously obtained in rodent and cat. No displacement was observed with WAY-100635 (1 mg/kg iv) but a blockade was observed when WAY100635 (1 mg/kg iv) was administered before the radiotracer. The blood profiles were reproducible between baselines acquisitions. The kinetic modelling using the two-tissue compartment model and k4=0 yielded the best results (i.e. lowest AIC and highest MSC). Test-retest of Ki was < 10%. In conclusion, if [18F]F13714 binds in vivo the high-affinity states of the 5-HT1A receptors, the modelling data and the competition studies suggest that it binds to the target in a quasi irreversible manner (ie very low k4), probably because of its particular high affinity

Synthesis, Radiosynthesis, and Biological Evaluation of Carbon-11 and Fluorine-18 Labeled Reboxetine Analogs: Potential Positron Emission Tomography Radioligands for in Vivo Imaging of the Norepinephrine Transporter

Reboxetine analogs with methyl and fluoroalkyl substituents at position 2 of the phenoxy ring 1–4 were synthesized. In vitro competition binding demonstrated that 1–4 have a high affinity for the norepinephrine transporter (NET) with K i ’s = 1.02, 3.14, 3.68, and 0.30 nM (vs [ 3 H]nisoxetine), respectively. MicroPET imaging in rhesus monkeys showed that the relative regional distribution of [ 11 C] 1 and [ 11 C] 4 is consistent with distribution of the NET in the brain, while [ 18 F] 2 and [ 18 F] 3 showed only slight regional differentiation in brain uptake. Especially, the highest ratios of uptake of [ 11 C] 1 in NET-rich regions to that in caudate were obtained at 1.30–1.45 at 45 min, and remained relatively constant over 85 min. Pretreatment of the monkey with the selective NET inhibitor, desipramine, decreased the specific binding for both [ 11 C] 1 and [ 11 C] 4 . PET imaging in awake monkeys suggested that anesthesia influenced the binding potential of [ 11 C] 1 and [ 11 C] 4 at the NET

Evaluation of [¹⁸F]2FP3 in pigs and non-human primates

International audienc

5-Iodo-A-85380, an α4β2 Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors

In an effort to develop selective radioligands for in vivo imaging of neuronal nicotinic acetylcholine receptors (nAChRs), we synthesized 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-iodo-A-85380) and labeled it with 125I and123I. Here we present the results of experiments characterizing this radioiodinated ligand in vitro. The affinity of 5-[125I]iodo-A-85380 for α4β2 nAChRs in rat and human brain is defined by K d values of 10 and 12 pM, respectively, similar to that of epibatidine (8 pM). In contrast to epibatidine, however, 5-iodo-A-85380 is more selective in binding to the α4β2 subtype than to other nAChR subtypes. In rat adrenal glands, 5-iodo-A-85380 binds to nAChRs containing α3 and β4 subunits with 1/1000th the affinity of epibatidine, and exhibits 1/60th and 1/190th the affinity of epibatidine at α7 and muscle-type nAChRs, respectively. Moreover, unlike epibatidine and cytisine, 5-[125I]iodo-A-85380 shows no binding in any brain regions in mice homozygous for a mutation in the β2 subunit of nAChRs. Binding of 5-[125I]iodo-A-85380 in rat brain is reversible, and is characterized by high specificity and a slow rate of dissociation of the receptor–ligand complex (t 1/2 for dissociation ∼2 h). These properties, along with other features observed previously in in vivo experiments (low toxicity, rapid penetration of the blood-brain barrier, and a high ratio of specific to nonspecific binding), suggest that this compound, labeled with 125I or 123I, is superior to other radioligands available for in vitro and in vivo studies of α4β2 nAChRs, respectively

Brain microglia activation and peripheral adaptive immunity in Parkinson’s disease: a multimodal PET study

Background Abnormal activation of immune system is an important pathogenesis of Parkinson’s disease, but the relationship between peripheral inflammation, central microglia activation and dopaminergic degeneration remains unclear. Objectives To evaluate the brain regional microglia activation and its relationship with clinical severity, dopaminergic presynaptic function, and peripheral inflammatory biomarkers related to adaptive immunity. Methods In this case–control study, we recruited 23 healthy participants and 24 participants with early-stage Parkinson’s disease. 18F-PBR06 PET/MR for microglia activation, 18F-FP-DTBZ for dopaminergic denervation, total account of T cells and subpopulations of T helper (Th1/Th2/Th17) cells, and the levels of serum inflammatory cytokines were assessed. Sanger sequencing was used to exclude the mix-affinity binders of 18F-PBR06-PET. Results Compared to healthy controls, patients with Parkinson’s disease had an increased 18F-PBR06-PET standardized uptake value ratio (SUVR) in the putamen, particularly in the ipsilateral side of the motor onset. 18F-PBR06-PET SUVR was positively associated with 18F-FP-DTBZ-PET SUVR in the brainstem and not associated with disease severity measured by Hoehn and Yahr stage, MDS-UPDRS III scores. Patients with Parkinson’s disease had elevated frequencies of Th1 cells and serum levels of IL10 and IL17A as compared to healthy controls. No significant association between peripheral inflammation markers and microglia activation in the brain of PD was observed. Conclusion Parkinson’s disease is associated with early putaminal microglial activation and peripheral phenotypic Th1 bias. Peripheral adaptive immunity might be involved in microglia activation in the process of neurodegeneration in PD indirectly, which may be a potential biomarker for the early detection and the target for immunomodulating therapy.Science, Faculty ofNon UBCPhysics and Astronomy, Department ofReviewedFacultyResearche