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Synthesis, F-18 radiolabeling, and microPET evaluation of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines as ligands of the corticotropin-releasing factor type-1 (CRF1) receptor.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2015 Aug 01; Vol. 23 (15), pp. 4286-4302. Date of Electronic Publication: 2015 Jun 19. - Publication Year :
- 2015
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Abstract
- A series of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines were synthesized and evaluated as potential positron emission tomography (PET) tracers for the corticotropin-releasing factor type-1 (CRF1) receptor. Compounds 27, 28, 29, and 30 all displayed high binding affinity (⩽1.2 nM) to the CRF1 receptor when assessed by in vitro competition binding assays at 23 °C, whereas a decrease in affinity (⩾10-fold) was observed with compound 26. The logP7.4 values of [(18)F]26-[(18)F]29 were in the range of ∼2.2-2.8 and microPET evaluation of [(18)F]26-[(18)F]29 in an anesthetized male cynomolgus monkey demonstrated brain penetrance, but specific binding was not sufficient enough to differentiate regions of high CRF1 receptor density from regions of low CRF1 receptor density. Radioactivity uptake in the skull, and sphenoid bone and/or sphenoid sinus during studies with [(18)F]28, [(18)F]28-d8, and [(18)F]29 was attributed to a combination of [(18)F]fluoride generated by metabolic defluorination of the radiotracer and binding of intact radiotracer to CRF1 receptors expressed on mast cells in the bone marrow. Uptake of [(18)F]26 and [(18)F]27 in the skull and sphenoid region was rapid but then steadily washed out which suggests that this behavior was the result of binding to CRF1 receptors expressed on mast cells in the bone marrow with no contribution from [(18)F]fluoride.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Binding, Competitive
Chemistry Techniques, Synthetic
Diagnostic Uses of Chemicals
Fluorine Radioisotopes pharmacokinetics
Humans
Ligands
Macaca fascicularis
Male
Radiopharmaceuticals chemical synthesis
Radiopharmaceuticals pharmacokinetics
Rats, Sprague-Dawley
Fluorine Radioisotopes chemistry
Isotope Labeling methods
Positron-Emission Tomography methods
Radiopharmaceuticals chemistry
Receptors, Corticotropin-Releasing Hormone metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 23
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26145817
- Full Text :
- https://doi.org/10.1016/j.bmc.2015.06.036