title: 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.
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.
authors.affiliation: Center for Systems Imaging, Department of Radiology and Imaging Sciences, Emory University, WWHC 209, 1841 Clifton Rd NE, Atlanta, GA 30329, USA. Electronic address: jstehou@emory.edu.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Stehouwer
authors.affiliation: Center for Systems Imaging, Department of Radiology and Imaging Sciences, Emory University, WWHC 209, 1841 Clifton Rd NE, Atlanta, GA 30329, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Birnbaum
authors.affiliation: Center for Systems Imaging, Department of Radiology and Imaging Sciences, Emory University, WWHC 209, 1841 Clifton Rd NE, Atlanta, GA 30329, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Voll
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owens
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Plott
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
authors.forename: Chase H
authors.initials: CH
authors.lastname: Bourke
authors.affiliation: Center for Systems Imaging, Department of Radiology and Imaging Sciences, Emory University, WWHC 209, 1841 Clifton Rd NE, Atlanta, GA 30329, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Wassef
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Clinton D
authors.initials: CD
authors.lastname: Kilts
authors.affiliation: Center for Systems Imaging, Department of Radiology and Imaging Sciences, Emory University, WWHC 209, 1841 Clifton Rd NE, Atlanta, GA 30329, USA; Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Goodman
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D060326:Chemistry Techniques, Synthetic; D064907:Diagnostic Uses of Chemicals; D005462:Fluorine Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D007553:Isotope Labeling / Q000379:methods*; D008024:Ligands; D008252:Macaca fascicularis; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D000099052:CRF Receptor, Type 1
chemical_list: D064907:Diagnostic Uses of Chemicals; D005462:Fluorine Radioisotopes; D008024:Ligands; D019275:Radiopharmaceuticals; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1
keywords: CRF-1 receptor; Corticotropin-releasing factor; F-18; Fluorine-18; PET imaging