We have subsequently extended this approach to look at the in vitro activity, in vivo efficacy and pharmacokinetics of an agonist molecule, interferon (IFN)-alpha 2b, fused to an AlbudAb. Here we describe this molecule and show that in this Z VAD FMK format AlbudAb half-life extension technology displays significant advantages in comparison with other methods of half-life extension, in particular genetic fusion to serum albumin. When compared directly IFN-alpha 2b fused to an Albudab shows higher potency, increased serum half-life and greater efficacy than human serum albumin fused to IFN-alpha 2b. AlbudAbs are therefore an ideal platform technology for creation
of therapeutics with agonist activity and long serum half-lives.”
“Introduction: alpha 7-nicotinic acetylcholine receptor (alpha 7-nAChR) is one of the major neuronal nAChR subtypes. alpha 7-nAChR is involved in variety of neuronal processes and disorders including schizophrenia and Alzheimer’s disease. A number of alpha 7-nAChR PET radioligands have been developed, but a quality radiotracer remains to be discovered.
Methods: High binding affinity alpha 7-nAChR ligands A-833834
and A-752274 were radiolabeled with C-11. Baseline and blockadp biodistribution studies in the mouse brain of [C-11]A-833834 (5-(6-(5-[C-11] Selleckchem PF-2341066 methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-1H-indole) and [C-11]A-752274 (2-(6-[C-11] methyl-3,6-diazabicyclo[3,2,0]heptan-3-yl)-7-(6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-9H-fluoren-9-one) were performed. [C-11]A-752274 was evaluated in a baseline baboon PET study.
Results: [C-11]A-833834 and [C-11]A-752274 were synthesized by radiomethylation of corresponding desmethyl precursors.
The radioligands were prepared with radiochemical yield of 12%-32%, high specific radioactivity (330-403 GB1/mu mol) and radiochemical check details purity>95%. Dissection studies with [C-11]A-833834 demonstrated low specific alpha 7-nAChR binding in the mouse brain. [C-11]A-752274 specifically (similar to 50%) labeled alpha 7-nAChR in the mouse thalamus. However, [(11)CA-752274 exhibited low brain uptake in baboon (%SUV<100).
Conclusion: Two novel alpha 7-nAChR ligands radioligands were synthesized and studied in animals. Specific binding of [C-11]A-833834 in the mouse brain is low due to the insufficient binding affinity of the radioligand. The very high binding affinity [C-11]A-752274 exhibited good specific binding in the alpha 7-nAChR-rich mouse brain regions. The low uptake of [C-11]A-752274 in the baboon brain is due to its high hydrophilicity, rapid metabolism or other properties. Future development of alpha 7-nAChR PET radioligands will be based on compounds with high binding affinities and good blood-brain barrier permeability. (C) 2013 Elsevier Inc. All rights reserved.