Member 1 (TRPV1) receptor is a nonselective, Ca2 permeable cation channel belonging to the TRP ion channel family members.1 TRPV1 is mainly expressed on a subpopulation of main sensory neurons in the dorsal root and trigeminal ganglia and their nociceptive terminals. Expression of functional TRPV1 receptors has also been demonstrated in different nonneuronal cell sorts, which include human skin cells,two urothelial cells,3 and pancreatic cells,4 and proof of an active population of TRPV1 receptors in the central nervous program (CNS) is emerging. Nevertheless, the extent to which these central and nonneuronal TRPV1 channels are expressed continues to be a subject of controversy, and their exact (patho)physiological function remains elusive.59 TRPV1 is pursued as a target for the improvement of a brand new class of antiinflammatory and analgesic drugs. Opening of TRPV1 channels expressed on sensory neurons, by agonists [e.g., capsaicin, resiniferatoxin (RTX), or anandamide], heat, or acidic pH,10 leads to depolarization of the cell membrane via calcium influx whereby painful stimuli are transmitted and pro2013 American Chemical SocietyTinflammatory neuropeptides like substance P and calcitonin generelated peptide are released.11,12 Hence, TRPV1 has been recommended to play an critical function in the pathogenesis of several pain conditions and chronic inflammatory disorders.13 In the CNS, TRPV1 regulates several functions in response to stress14 and mediates synaptic plasticity, which highlights its potential function in the control of emotional responses, learning, and epileptic activity.15 Moreover, 5-Acetylsalicylic acid web accumulating evidence suggests that TRPV1 channels may contribute to the pathogenesis of febrile alpha-D-glucose Technical Information seizures, stroke, and neurodegenerative brain problems like Parkinson’s disease.16,17 These CNSrelated observations could indicate new prospective therapeutic applications, but much more analysis is necessary to elucidate the exact (pathological) part of these central TRPV1 receptors.Received: December 20, 2012 Accepted: February six, 2013 Published: February 19,dx.doi.org/10.1021/cn300233v | ACS Chem. Neurosci. 2013, four, 624ACS Chemical NeuroscienceResearch ArticleFigure 1. Cinnamic acid derivatives. Structure of compounds 1 and 2 and synthesis of compound 3. (i) 2Fluoroethyl tosylate, Cs2CO3, 5 h at 120 .Figure 2. Synthesis of cinnamic acid derivative DVV24. (i) EDCI, HOBt, 16 h at space temperature.Positron emission tomography (PET) tracers can serve as potent tools in studying the efficacy of therapeutics that target TRPV1 and in investigating altered TRPV1 levels beneath pathophysiological conditions. Previously, we’ve synthesized and evaluated [11C]SB366791, a distinct TRPV1 PET radioligand. On the other hand, its clinical use is doubtful as a result of its somewhat low binding affinity (280 56 nM) for human TRPV1 (hTRPV1).18 Consequently, we aimed to create PET radioligands that show larger binding affinities. After a literature survey, quite a few potent TRPV1 antagonists belonging to diverse structural classes have been selected, which includes cinnamic acid derivatives,19 aminoquinazolines,20 and urea derivatives.21 To let radiolabeling, a number of these molecules essential little structural modifications. Furthermore, the chlorine atom in SB366791 was substituted having a trifluoromethyl group. It has been shown that the nature on the 4position ring substituent in other structurally related compounds plays an important role in figuring out the activity for TRPV1. More hydrophobic substituents such as a trifluo.