Johan Sandell

Characterization of AZD4694, a novel fluorinated Abeta plaque neuroimaging PET radioligand

J. Neurochem. (2010) 114, 784–794.

Synthesis and evaluation of 2-pyridylbenzothiazole, 2-pyridylbenzoxazole and 2-pyridylbenzofuran derivatives as 11C-PET imaging agents for β-amyloid plaques

The syntheses and SAR of new series of beta-amyloid binding agents are reported. The effort to optimize signal-to-background ratios for these ligands are described. Compounds 8, 21 and 30 displayed desirable lipophilicity and pharmacokinetic properties. Compounds 8 and 21 were evaluated with in vitro autoradiographic studies and in vivo in APP/PS1 transgenic mice. It is shown that it was possible to increase the signal-to-background ratios compared to PIB 1, as demonstrated by compounds 8 and 21.

Synthesis and evaluation of pyridylbenzofuran, pyridylbenzothiazole and pyridylbenzoxazole derivatives as 18F-PET imaging agents for β-amyloid plaques

The synthesis and SAR of new β-amyloid binding agents are reported. Evaluation of important properties for achieving good signal-to-background ratio is described. Compounds 27, 33, and 36 displayed desirable lipophilic and pharmacokinetic properties. Compound 27 was further evaluated with autoradiographic studies in vitro on human brain tissue and in vivo in Tg2576 mice. Compound 27 showed an increased signal-to-background ratio compared to flutemetamol 4, indicating its suitability as PET ligand for β-amyloid deposits in AD patients. The preparation of the corresponding (18)F-labeled PET radioligand of compound 27 is presented.

Low background and high contrast PET imaging of amyloid-β with [11C]AZD2995 and [11C]AZD2184 in Alzheimer’s disease patients

PurposeThe aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer’s disease (AD).MethodsIn vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [11C]AZD2995 and [11C]AZD2184 in three healthy control subjects and seven AD patients.ResultsAZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [3H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [11C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [11C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus. ConclusionBoth AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [11C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [11C]AZD2995. However, the very low nonspecific binding of [11C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy.

Synthesis, Radiolabeling, and In Vivo Pharmacokinetic Evaluation of the Amyloid Beta Radioligand [11C]AZD4694 in Nonhuman Primates

Purpose[18F]AZD4694 (2-(2-18F-fluoro-6-(methylamino)-3-pyridyl)benzofuran-5-ol) is a radioligand suitable for imaging of amyloid beta deposits in the living human brain using positron emission tomography (PET). Here, we report the preparation and pharmacokinetic profile of its carbon-11 (t1/2u2009=u200920.4xa0min) labeled isotopolog [11C]AZD4694 and compare [11C]AZD4694 with the hitherto most widely applied amyloid PET radioligand [11C]Pittsburgh Compound B (PiB).ProceduresThe immediate unlabeled precursor to [11C]AZD4694 was prepared in a four-step convergent synthesis. Subsequent N-11C-methylation of this precursor with [11C]methyl iodide yielded [11C]AZD4694, which after isolation and formulation was injected into cynomolgus monkeys. The radioactivity in nonhuman primate brain following injection of [11C]AZD4694 and [11C]PiB was measured using PET.Results[11C]AZD4694 was prepared in a 60xa0% incorporation yield. In a head to head comparison with [11C]PiB, it appeared that [11C]AZD4694 displayed slightly lower nonspecific binding in white matter than [11C]PiB as well as more rapid pharmacokinetics in the brain.ConclusionsThe advantageous pharmacokinetic profile and low nonspecific binding render [11C]AZD4694 a promising PET radioligand for imaging of amyloid beta in the human brain with PET.

Preparation of [3H]fluoroethyl tosylate and its use in the labelling of the dopamine transporter radioligand [3H]FE-PE2I

[(3) H]Fluoroethyl tosylate, a novel alkylating tritium labelling agent, was synthesized from tritium gas with high specific activity and with 99% radiochemical purity. [(3) H]Fluoroethyl tosylate was applied in the tritium labelling of the dopamine transporter radioligand [(3) H]FE-PE2I.

Carbon-14 radiosynthesis of the benzofuran derivative and β-amyloid plaque neuroimaging positron emission tomography radioligand AZD4694

In support of a metabolite study, the β-amyloid plaque neuroimaging positron-emission tomography radioligand AZD4694 was labeled with carbon-14 in 10 radiosynthetic steps starting from radiolabeled carbon dioxide. [(14)C]AZD4694 was labeled in the benzofuran heterocycle with a specific activity of 2.1u2009GBq/mmol and with a radiochemical purity of >99%. The described synthesis constitutes a general method to carbon-14-labeled substituted benzofurans.

[18F]AZD4694—A new PET radioligand for sensitive detection of β-amyloid deposits

PET radioligands that bind selectively to β-amyloid plaques (Ab) are imaging tools having potential to support the clinical diagnosis of Alzheimers disease (AD) and the evaluation of new drugs aiming to modify amyloid plaque load. For extended clinical use there is a particular need for radioligands labeled with fluorine-18, a radionuclide allowing for central synthesis followed by wide distribution. The development of fluorinated radioligands is however challenging due to the lipophilic nature of aromatic fluorine, rendering fluorinated ligands more prone to have high unspecific white matter binding. We have developed the new potential radioligand, AZD4694 with high affinity for β-amyloid fibrils in vitro (Kd 2.3±0.3 nM). Here we present the preclinial characterization in vitro and in vivo. In cortical sections from human AD brain [H]labeled AZD4694 bound selectively to β-amyloid deposits in gray matter with low level of non-specific binding to plaque devoid white matter. Ex vivo autoradiography in aged tg2576 mice showed that [H]AZD4694 selectively labelled β-amyloid plaques with low levels of nonspecific binding. Congo red labelling in adjacent sections from the same brain confirmed that [H]AZD4694 and Congo red labeled apparently identical structures. The suitability of [F]AZD4694 as a potential PET radioligand was examined further in young cynomolgus monkeys not expected to have amyloid deposits. [F]AZD4694 rapidly entered the monkey brain with a peak exposure of about 5% of the total injected radioactivity. Within 2 min after injection. Brain radioactivity cleared rapidly thereafter and was at a homogenous low level throughout the PETmeasurement. Taken together, the preclinical profile of AZD4694 suggests that fluorine-18 labelled AZD4694 have potential for selective PETvisualization of β-amyloid deposits in the living human brain.