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. Issue 15 (1st August 2015)

• Record Type: Journal Article
• Authors: Stehouwer, Jeffrey S.; Birnbaum, Matthew S.; Voll, Ronald J.; Owens, Michael J.; Plott, Susan J.; Bourke, Chase H.; Wassef, Michael A.; Kilts, Clinton D.; Goodman, Mark M.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 15(2015)
• Page Start: 4286
• Page End: 4302
• Publication Date: 2015-08-01
• Subjects: CRF corticotropin-releasing factor -- CRF1 CRF type-1 receptor1 -- PET positron emission tomography -- SPECT single-photon emission computed tomography -- BBB blood–brain barrier -- DMA dimethylacetamide -- PEG polyethylene glycol -- SUV standard uptake value2–4 -- TACs time–activity curves -- ROIs regions of interest -- CPCU chemical processing control unit -- rcy radiochemical yield -- EOB end-of-bombardment; Corticotropin-releasing factor -- CRF-1 receptor -- PET imaging -- F-18 -- Fluorine-18; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.06.036
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 log P 7.4 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- d 8, 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.