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Synthesis and evaluation of radioiodine-labelled CP-118,954 for the in-vivo imaging of acetylcholinesterase.
- Source :
-
Nuclear medicine communications [Nucl Med Commun] 2007 Jul; Vol. 28 (7), pp. 561-6. - Publication Year :
- 2007
-
Abstract
- Objectives: Alzheimer's disease (AD) is characterized by reduced acetylcholinesterase (AChE) activity in the post-mortem tissues of AD patients. Therefore, AChE has been an attractive target for the diagnosis of AD. In the present study, 5,7-dihydro-3-[2-(1-(phenylmethyl)-4-piperidinyl)ethyl]-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one (CP-118,954), a potent AChE inhibitor, was labelled with radioiodine and evaluated as an AChE imaging agent for SPECT.<br />Methods: Radioiodine-labelled CP-118,954 was prepared from CP-144,885 and [(125)I]iodobenzyl bromide, and anti-AChE activities of iodine-substituted CP-118,954 were measured. Metabolism studies were carried out in samples of blood and whole brain of mice injected with 2-[(123)I]iodo-CP-118,954 ((123)I-1). Tissue distribution studies were also performed in mice injected with I-1, and samples of blood, thyroid, stomach, and brain tissue (cerebellum, striatum and cortex) were removed, weighed and counted.<br />Results: Of the ligands, 2-iodo-CP-118,954 exhibited higher binding affinity for AChE (IC50=24 nM) than the other positional isomers. 2-[(125)I]Iodo-CP-118,954 was found to have a lipophilicity (log P=2.1) favouring brain permeability and metabolic stability in mouse brain, but a marginal target (striatum) to non-target (cerebellum) uptake ratio (1.1) in mouse brain.<br />Conclusion: This result demonstrates that 2-[(125)I]iodo-CP-118,954 may be unsuitable for AChE imaging. These findings suggest that radioligands suitable for AChE imaging should have not only a specific structure but also a sub-nanomolar to low nanomolar IC50.
- Subjects :
- Animals
Cholinesterase Inhibitors chemical synthesis
Cholinesterase Inhibitors pharmacokinetics
Drug Evaluation, Preclinical
Iodine Radioisotopes chemistry
Isotope Labeling
Isoxazoles chemistry
Male
Metabolic Clearance Rate
Mice
Mice, Inbred ICR
Piperidines chemistry
Radionuclide Imaging
Radiopharmaceuticals chemical synthesis
Radiopharmaceuticals pharmacokinetics
Tissue Distribution
Acetylcholinesterase metabolism
Brain diagnostic imaging
Brain enzymology
Iodine Radioisotopes pharmacokinetics
Isoxazoles pharmacokinetics
Piperidines pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 0143-3636
- Volume :
- 28
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Nuclear medicine communications
- Publication Type :
- Academic Journal
- Accession number :
- 17538398
- Full Text :
- https://doi.org/10.1097/MNM.0b013e328194f1f7