Radiosynthesis and initial characterization of a PDE10A specific PET tracer [18F]AMG 580 in non-human primates  Dah-Ren Hwang, Essa Hu, Jennifer R. Allen, Carl Davis, James Treanor, Silke Miller, Hang Chen, Bingzhi Shi, Tanjorie K. Narayanan, Olivier Barret, David Alagille, Zhigang Yu, Mark Slifstein  Nuclear Medicine and Biology  Volume 42, Issue 8, Pages 654-663 (August 2015) DOI: 10.1016/j.nucmedbio.2015.04.004 Copyright © 2015 Elsevier Inc. Terms and Conditions

Fig. 1 Reaction scheme of [18F]AMG 580. Nuclear Medicine and Biology 2015 42, 654-663DOI: (10.1016/j.nucmedbio.2015.04.004) Copyright © 2015 Elsevier Inc. Terms and Conditions

Fig. 2 Representative autoradiographic images of [3H]AMG 580 binding to coronal baboon brain sections. (A) Striatal areas and globus pallidus are prominently labeled compared to low binding in cortex and amygdala. (B) Non-specific binding as defined by displacement with 10μM PDE10A inhibitor 1 was low. Labeling intensity scale ranges from 0 (white) to 30cpm/mm2 (black). Scale bar=10mm. AMY=amygdala, CAU=caudate nucleus, CTX=cortex, GP=globus pallidus, PUT=putamen. Nuclear Medicine and Biology 2015 42, 654-663DOI: (10.1016/j.nucmedbio.2015.04.004) Copyright © 2015 Elsevier Inc. Terms and Conditions

Fig. 3 Mean fraction of plasma activity corresponding to the parent tracer over time after injection of [18F]AMG 580. Rhesus ▲ (n=2) and baboon ○ (n=3). Nuclear Medicine and Biology 2015 42, 654-663DOI: (10.1016/j.nucmedbio.2015.04.004) Copyright © 2015 Elsevier Inc. Terms and Conditions

Fig. 4 Representative analytical HPLC chromatograms of radioactive metabolites and parent tracer in plasma samples. The ordinate axis is in arbitrary unites (AU). All radioactive metabolites eluted before the parent tracer. Nuclear Medicine and Biology 2015 42, 654-663DOI: (10.1016/j.nucmedbio.2015.04.004) Copyright © 2015 Elsevier Inc. Terms and Conditions

Fig. 5 [18F]AMG 580 brain PET images obtained in a male Rhesus monkey (top panel) and a female baboon (bottom panel). The PET images are summed over 180min. Top: The baseline images (row 2) showed intense tracer uptake in the striatum, a region known to have high expression of PDE10A. The 1 and 3mg/kg blocking scan images are shown in rows 3 and 4. A dose-dependent decrease of striatal uptake was observed. The corresponding MRI images are shown at the top. Bottom: Summed image data in the baboon showing similar high uptake in striatum as observed in the Rhesus. Nuclear Medicine and Biology 2015 42, 654-663DOI: (10.1016/j.nucmedbio.2015.04.004) Copyright © 2015 Elsevier Inc. Terms and Conditions

Fig. 6 Rhesus monkey time-activity-curves of the target regions (globus pallidus, GP; putamen, PUT; caudate, CAU) and the reference tissue (midbrain, MID) at baseline (left), and following blocking with 1mg/kg (middle) and 3mg/kg (right) doses. Data are normalized to injected activity. Regions are GP (▲), PUT (▼), CAD (◆), and MID (●). Markers represent measured ROI activity. Continuous curves are the 2TC fits. Nuclear Medicine and Biology 2015 42, 654-663DOI: (10.1016/j.nucmedbio.2015.04.004) Copyright © 2015 Elsevier Inc. Terms and Conditions

Fig. 7 Time-activity-curves of low binding regions of Rhesus monkey (left) and baboon (right): MID (▲), frontal cortex (●), THA (▼), and cerebellum (◆). Activity values are normalized to the peak activity in cerebellum. Nuclear Medicine and Biology 2015 42, 654-663DOI: (10.1016/j.nucmedbio.2015.04.004) Copyright © 2015 Elsevier Inc. Terms and Conditions

Fig. 8 Scatchard plot of bound (B) vs bound/free (B/F) ratio. Nuclear Medicine and Biology 2015 42, 654-663DOI: (10.1016/j.nucmedbio.2015.04.004) Copyright © 2015 Elsevier Inc. Terms and Conditions

Fig. 9 Dynamic [18F]AMG 580 whole-body PET image (sagittal view). The rows are at three different levels through the body and the columns show the evolution of the activity concentration over time (scan 1, 3, 5, 7, 9 and 11). Nuclear Medicine and Biology 2015 42, 654-663DOI: (10.1016/j.nucmedbio.2015.04.004) Copyright © 2015 Elsevier Inc. Terms and Conditions

Fig. 10 Non-decay corrected [18F]AMG 580 time activity curves of the identified source organs from a baboon whole body scan, expressed as percent of the injected dose. Nuclear Medicine and Biology 2015 42, 654-663DOI: (10.1016/j.nucmedbio.2015.04.004) Copyright © 2015 Elsevier Inc. Terms and Conditions