title: New transient receptor potential vanilloid subfamily member 1 positron emission tomography radioligands: synthesis, radiolabeling, and preclinical evaluation.
abstract: The transient receptor potential vanilloid subfamily member 1 (TRPV1) cation channel is known to be involved in pain nociception and neurogenic inflammation, and accumulating evidence suggests that it plays an important role in several central nervous system (CNS)-related disorders. TRPV1-specific positron emission tomography (PET) radioligands can serve as powerful tools in TRPV1-related (pre)clinical research and drug design. We have synthesized several potent TRPV1 antagonists and accompanying precursors for radiolabeling with carbon-11 or fluorine-18. The cinnamic acid derivative [(11)C]DVV24 and the aminoquinazoline [(18)F]DVV54 were successfully synthesized, and their biological behavior was studied. In addition, the in vivo behavior of a (123)I-labeled analogue of iodo-resiniferatoxin (I-RTX), a well-known TRPV1 antagonist, was evaluated. The binding affinities of DVV24 and DVV54 for human TRPV1 were 163 ± 28 and 171 ± 48 nM, respectively. [(11)C]DVV24, but not [(18)F]DVV54 or (123)I-RTX, showed retention in the trigeminal nerve, known to abundantly express TRPV1. Nevertheless, it appears that ligands with higher binding affinities will be required to allow in vivo imaging of TRPV1 via PET.
authors: Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Campus Gasthuisberg O&N2, Herestraat 49 box 821, 3000 Leuven, Belgium.
authors: Daisy
authors: D
authors: van Veghel
authors: Jan
authors: J
authors: Cleynhens
authors: Larry V
authors: LV
authors: Pearce
authors: Ian A
authors: IA
authors: DeAndrea-Lazarus
authors: Peter M
authors: PM
authors: Blumberg
authors: Koen
authors: K
authors: Van Laere
authors: Alfons
authors: A
authors: Verbruggen
authors: Guy
authors: G
authors: Bormans
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D011869:Radioligand Assay / Q000379:methods*; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human