INTRODUCTION: The transient receptor potential vanilloid subfamily member 1 (TRPV1) receptor, a non-selective cation channel, is known for its key role in pain nociception and neurogenic inflammation. TRPV1 expression has been demonstrated in diverse tissues and an essential role for TRPV1 in various disorders has been suggested. A TRPV1-specific PET-radioligand can serve as a useful tool for further in vivo research in animals and directly in humans. In this study, we report the synthesis and biological evaluation of a carbon-11 labelled analogue of N-(3-methoxyphenyl)-4-chlorocinnamide (SB366791) which was reported as a specific high-affinity antagonist for TRPV1. METHODS: The new tracer was evaluated with respect to log D and biodistribution in control, pretreated and TRPV1⁻/⁻ mice. The percentage of radiometabolites of [¹¹C]SB366791 was determined in mouse plasma and brain. RESULTS: [¹¹C] SB366791 was obtained in good yield (69%±11%; isolated amounts 3034-5032MBq) and high specific activity (390±215 GBq/μmol). The tracer was efficiently cleared from blood and all major organs via hepatobiliary and renal pathways. Initial brain uptake was high (1.6% ID) and wash-out from brain was rapid. The retention of [¹¹C] SB366791 in the trigeminal nerve of control mice was prominent. The in vitro binding affinity of SB366791 was determined to be 280±56 nM and 780±140 nM for human and rat TRPV1, respectively. CONCLUSIONS: [¹¹C] SB366791 has favourable biodistribution characteristics in mice. However the obtained low binding affinity for TRPV1 may not be sufficient to use the current compound as PET tracer.
INTRODUCTION: The transient receptor potential vanilloid subfamily member 1 (TRPV1) receptor, a non-selective cation channel, is known for its key role in pain nociception and neurogenic inflammation. TRPV1 expression has been demonstrated in diverse tissues and an essential role for TRPV1 in various disorders has been suggested. A TRPV1-specific PET-radioligand can serve as a useful tool for further in vivo research in animals and directly in humans. In this study, we report the synthesis and biological evaluation of a carbon-11 labelled analogue of N-(3-methoxyphenyl)-4-chlorocinnamide (SB366791) which was reported as a specific high-affinity antagonist for TRPV1. METHODS: The new tracer was evaluated with respect to log D and biodistribution in control, pretreated and TRPV1⁻/⁻ mice. The percentage of radiometabolites of [¹¹C]SB366791 was determined in mouse plasma and brain. RESULTS: [¹¹C] SB366791 was obtained in good yield (69%±11%; isolated amounts 3034-5032MBq) and high specific activity (390±215 GBq/μmol). The tracer was efficiently cleared from blood and all major organs via hepatobiliary and renal pathways. Initial brain uptake was high (1.6% ID) and wash-out from brain was rapid. The retention of [¹¹C] SB366791 in the trigeminal nerve of control mice was prominent. The in vitro binding affinity of SB366791 was determined to be 280±56 nM and 780±140 nM for human and ratTRPV1, respectively. CONCLUSIONS: [¹¹C] SB366791 has favourable biodistribution characteristics in mice. However the obtained low binding affinity for TRPV1 may not be sufficient to use the current compound as PET tracer.
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