INTRODUCTION: Gamma amino butyric acid type A (GABA(A)) receptors are involved in a variety of neurological and psychiatric diseases, which have promoted the development and use of radiotracers for positron emission tomography imaging. Radiolabeled benzodiazepine antagonists such as flumazenil have most extensively been used for this purpose so far. Recently, the non-benzodiazepine pyrazolopyrimidine derivative indiplon with higher specificity for the alpha(1) subtype of the GABA(A) receptor has been introduced for treatment of insomnia. The aim of this study was the development and biological evaluation of an (18)F-labeled derivative of indiplon. METHODS: Both [(18)F]fluoro-indiplon and its labeling precursor were synthesized by two-step procedures starting from indiplon. The radiosynthesis of [(18)F]fluoro-indiplon was performed using the bromoacetyl precursor followed by multiple-stage purification using semipreparative HPLC and solid phase extraction. Stability, partition coefficients, binding affinities and regional brain binding were determined in vitro. Biodistribution and radiotracer metabolism were studied in vivo. RESULTS: [(18)F]Fluoro-indiplon was readily accessible in good yields (38-43%), with high purity and high specific radioactivity (>150 GBq/micromol). It displays high in vitro stability and moderate lipophilicity. [(18)F]Fluoro-indiplon has an affinity to GABA(A) receptors comparable to indiplon (K(i)=8.0 nM vs. 3.4 nM). In vitro autoradiography indicates high [(18)F]fluoro-indiplon binding in regions with high densities of GABA(A) receptors. However, ex vivo autoradiography and organ distribution studies show no evidence of specific binding of [(18)F]fluoro-indiplon. Furthermore, the radiotracer is rapidly metabolized with high accumulation of labeled metabolites in the brain. CONCLUSIONS: Although [(18)F]fluoro-indiplon shows good in vitro features, it is not suitable for in vivo imaging studies because of its metabolism. Structural modifications are needed to develop derivatives with higher in vivo stability.
INTRODUCTION: Gamma amino butyric acid type A (GABA(A)) receptors are involved in a variety of neurological and psychiatric diseases, which have promoted the development and use of radiotracers for positron emission tomography imaging. Radiolabeled benzodiazepine antagonists such as flumazenil have most extensively been used for this purpose so far. Recently, the non-benzodiazepinepyrazolopyrimidine derivative indiplon with higher specificity for the alpha(1) subtype of the GABA(A) receptor has been introduced for treatment of insomnia. The aim of this study was the development and biological evaluation of an (18)F-labeled derivative of indiplon. METHODS: Both [(18)F]fluoro-indiplon and its labeling precursor were synthesized by two-step procedures starting from indiplon. The radiosynthesis of [(18)F]fluoro-indiplon was performed using the bromoacetyl precursor followed by multiple-stage purification using semipreparative HPLC and solid phase extraction. Stability, partition coefficients, binding affinities and regional brain binding were determined in vitro. Biodistribution and radiotracer metabolism were studied in vivo. RESULTS: [(18)F]Fluoro-indiplon was readily accessible in good yields (38-43%), with high purity and high specific radioactivity (>150 GBq/micromol). It displays high in vitro stability and moderate lipophilicity. [(18)F]Fluoro-indiplon has an affinity to GABA(A) receptors comparable to indiplon (K(i)=8.0 nM vs. 3.4 nM). In vitro autoradiography indicates high [(18)F]fluoro-indiplon binding in regions with high densities of GABA(A) receptors. However, ex vivo autoradiography and organ distribution studies show no evidence of specific binding of [(18)F]fluoro-indiplon. Furthermore, the radiotracer is rapidly metabolized with high accumulation of labeled metabolites in the brain. CONCLUSIONS: Although [(18)F]fluoro-indiplon shows good in vitro features, it is not suitable for in vivo imaging studies because of its metabolism. Structural modifications are needed to develop derivatives with higher in vivo stability.