Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates various biological processes by phosphorylating protein substrates. Dysregulation of GSK-3 is linked to a variety of diseases, including malignancies, diabetes, and neurodegenerative disorders. Moreover, GSK-3 hyperactivity is a potential contributing factor in Alzheimer's disease, suggesting that GSK-3 inhibition may offer therapeutic benefits. Herein, we report the synthesis and evaluation of five 11C-labeled imidazolyl pyrimidine analogues [11C]13a-e (codenamed AZ12646326, AZ12646603, AZ12656261, AZ12977360, and AZ12943203) as novel radioligands for positron emission tomography (PET) imaging of GSK-3. Pharmacological assays showed that compounds 13a-e exhibited high in vitro binding affinity to GSK-3β, with Ki values ranging from 2.49 to 4.95 nM. In vitro autoradiography confirmed high levels of specific binding in GSK-3-rich regions of the rodent brain, highlighting the promising imaging properties of these analogues. Radiosynthesis of [11C]13a-e was achieved via palladium-promoted carbonylation reactions with [11C]carbon monoxide, with excellent radiochemical purity (>99%). However, PET imaging studies in nonhuman primates in vivo showed low brain uptake of these radioligands, and [11C]13e was identified as a P-glycoprotein substrate. This study offers valuable insights for optimizing future GSK-3-targeted PET tracers based on the imidazolyl pyrimidine scaffold.

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer's disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [18F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [3H]OXD-2115, and in silico models were used to predict brain uptake. [18F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies.

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer’s disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity 4-repeat (4R)-tau PET radiopharmaceutical for imaging non-AD tauopathies exists. Herein, the properties of analogues of a first-in-class 4R-tau lead, [18F]OXD-2115, are described. Over 150 analogues of OXD-2115 were synthesized and screened for tau affinity in vitro against [3H]OXD-2115, and in silico models were used to predict brain uptake. [18F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies.

CBD-2115 was selected from a library of 148 compounds based on a pyridinyl-indole scaffold as a first-in-class 4R-tau radiotracer. In vitro binding assays showed [3H]CBD-2115 had a KD value of 6.9 nM and a nominal Bmax of 500 nM in 4R-tau expressing P301L transgenic mouse tissue. In binding assays with human brain tissue homogenates, [3H]CBD-2115 has a higher affinity (4.9 nM) for progressive supranuclear palsy specific 4R-tau deposits than [3H]flortaucipir (45 nM) or [3H]MK-6240 (>50 nM). [18F]CBD-2115 was reliably synthesized (3-11% radiochemical yield with molar activity of 27-111 GBq/μmol and >97% radiochemical purity). Dynamic PET imaging was conducted in mice, rats, and nonhuman primates, and all species showed initial brain uptake of 0.5-0.65 standardized uptake value with fast clearance from normal tissues. [3H]CBD-2115 could be a useful lead radioligand for further research in 4R-tauopathies, and PET radiotracer development will focus on improving brain uptake and binding affinity.

LRRK2 (leucine-rich repeat kinase 2) has recently been proven to be a promising drug target for Parkinson’s disease (PD) due to an apparent enhanced activity caused by mutations associated with familial PD. To date, there have been no reports in which a LRRK2 inhibitor has been radiolabeled and used for in in vitro or in vivo studies of LRRK2. In the present study, we radiolabeled the LRRK2 ligand, LRRK-IN-1, for the purposes of performing in vitro (IC50, K d , B max, autoradiography) and in vivo (biodistribution, and blocking experiments) evaluations in rodents and human striatum tissues.

[(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.

Purpose [ 18 F]AZD4694 (2-(2- 18 F-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 ( t 1 / 2 = 20.4 min) labeled isotopolog [ 11 C]AZD4694 and compare [ 11 C]AZD4694 with the hitherto most widely applied amyloid PET radioligand [ 11 C]Pittsburgh Compound B (PiB). Procedures The immediate unlabeled precursor to [ 11 C]AZD4694 was prepared in a four-step convergent synthesis. Subsequent N - 11 C-methylation of this precursor with [ 11 C]methyl iodide yielded [ 11 C]AZD4694, which after isolation and formulation was injected into cynomolgus monkeys. The radioactivity in nonhuman primate brain following injection of [ 11 C]AZD4694 and [ 11 C]PiB was measured using PET. Results [ 11 C]AZD4694 was prepared in a 60 % incorporation yield. In a head to head comparison with [ 11 C]PiB, it appeared that [ 11 C]AZD4694 displayed slightly lower nonspecific binding in white matter than [ 11 C]PiB as well as more rapid pharmacokinetics in the brain. Conclusions The advantageous pharmacokinetic profile and low nonspecific binding render [ 11 C]AZD4694 a promising PET radioligand for imaging of amyloid beta in the human brain with PET.

PURPOSE:The 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).METHODS:In 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 [(11)C]AZD2995 and [(11)C]AZD2184 in three healthy control subjects and seven AD patients.RESULTS:AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [(3)H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [(11)C]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 [(11)C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus.CONCLUSION:Both 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 [(11)C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [(11)C]AZD2995. However, the very low nonspecific binding of [(11)C]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.

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 2.1 GBq/mmol and with a radiochemical purity of >99%. The described synthesis constitutes a general method to carbon-14-labeled substituted benzofurans.

[14C]Formaldehyde was synthesized by reducing 14CO2 at ambient temperature with Schwartz's reagent. The [14C]formaldehyde was then used in the radiosynthesis of high specific activity (2.1 GBq/mmol) [14C]hydrochlorothiazide via cyclization of 4‐amino‐5‐chloro‐1,3‐benzenedisulfonamide.

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 18F-labeled PET radioligand of compound 27 is presented.