Phosphodiesterase 10A (PDE10A) plays a central role in striatal signaling and is implicated in several neuropsychiatric disorders, such as movement disorders and schizophrenia. We performed initial brain kinetic modeling of the novel PDE10A tracer 18 F-JNJ-42259152 (2-[[4-[1-(2-18 F-fluoroethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]phenoxy]methyl]-3,5-dimethyl-pyridine) and studied test-retest reproducibility in healthy volunteers. Methods: Twelve healthy volunteers (5 men, 7 women; age range, 42-77 y) were scanned dynamically up to 135 min after bolus injection of 172.5 6 10.3 MBq of 18 F-JNJ42259152. Four volunteers (2 men, 2 women) underwent retest scanning, with a mean interscan interval of 37 d. Input functions and tracer parent fractions were determined using arterial sampling and high-performance liquid chromatography analysis. Volumes of interest for the putamen, caudate nucleus, ventral striatum, substantia nigra, thalamus, frontal cortex, and cerebellum were delineated using individual volumetric T1 MR imaging scans. Onetissue (1T) and 2-tissue (2T) models were evaluated to calculate total distribution volume (V T ). Simplified models were also tested to calculate binding potential (BP ND ), including the simplified reference tissue model (SRTM) and multilinear reference tissue model, using the frontal cortex as the optimal reference tissue. The stability of V T and BP ND was assessed down to a 60-min scan time. Results: The average intact tracer half-life in blood was 90 min. The 2T model V T values for the putamen, caudate nucleus, ventral striatum, substantia nigra, thalamus, frontal cortex, and cerebellum were 1.54 6 0.37, 0.90 6 0.24, 0.64 6 0.18, 0.42 6 0.09, 0.35 6 0.09, 0.30 6 0.07, and 0.36 6 0.12, respectively. The 1T model provided significantly lower V T values, which were well correlated to the 2T V T . SRTM BP ND values referenced to the frontal cortex were 3.45 6 0.43, 1.78 6 0.35, 1.10 6 0.31, and 0.44 6 0.09 for the respective target regions putamen, caudate nucleus, ventral striatum, and substantia nigra, with similar values for the multilinear reference tissue model. Good correlations were found for the target regions putamen, caudate nucleus, ventral striatum, and substantia nigra between the 2T-compartment model BP ND and the SRTM BP ND (r 5 0.57, 0.82, 0.70, and 0.64, respectively). SRTM BP ND using a 90-and 60-min acquisition interval showed low bias. Test-retest variability was 5%-19% for 2T V T and 5%-12% for BP ND SRTM. Conclusion: Kinetic modeling of 18 F-JNJ-42259152 shows that PDE10A activity can be reliably quantified and simplified using a reference tissue model with the frontal cortex as reference and a 60-min acquisition period.Key Words: PDE10A; PET; radioligand; 18 F; phosphodiesterase J Nucl Med 2013; 54:1285 54: -1293 54: DOI: 10.2967 Phosphodi esterase 10A (PDE10A) is a dual-substrate enzyme with a restricted distribution, predominantly in the human brain in medium spiny neurons of the striatum, the substantia nigra, the nucleus accumbens and olfactory tuberculum (1)...

In humans, (18)F-JNJ42259152 has an appropriate distribution, brain kinetics and safety. The estimated effective dose was within WHO class IIb with low interindividual variability. Therefore, the tracer is suitable for further kinetic evaluation in humans.