Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d] imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography-tandem mass spectrometry technology. [ 3 H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [18 F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.

Cadmium Zinc Telluride, or CZT, cameras offer dual-isotope imaging capabilities impossible to duplicate using any other preclinical molecular imaging system. This new technology will enable the investigation of multiple biological processes in parallel and open new areas in research and drug development. The dual-isotope capability is due to the improved energy resolution of CZT (4.5% for 99m Tc), which is 2-3 times better than in existing systems. This improved energy resolution allows for the rejection of more scattered photons, yielding higher contrast images. In addition, CZT provides increased sensitivity compared to traditional pixellated NaI(Tl) systems due to the absence of any escape peaks. These properties combine to give a higher sensitivity detector with significantly improved contrast. The present work demonstrates the use of CZT in dual-isotope imaging of mice using two radiopharmaceuticals with very close energy peaks. These included 99m Tc-labelled MDP (bone agent) and 123 I (thyroid) and a mouse bone ( 99m Tc-MDP) image with a 57 Co fiducial marker. The results show the first ever simultaneous 99m Tc / 123 I mouse images. The individual isotope peaks showed significant separation and yielded an image with the thyroid (2-3 mm) clearly distinguished from the bone structure. GM-I's new FLEX Triumph™ Pre-clinical system is the first in the field to offer CZT SPECT detectors.

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Introduction: Potent, selective, and orally available small molecule inhibitors of the p53 regulator MDM2 represent a promising class of therapeutics. When applied to p53WT tumors, MDM2 inhibitors disrupt the MDM2-p53 interaction, thereby activating the p53 pathway and inducing cell cycle arrest and apoptosis. The aim of this study was to evaluate two clinically available PET tracers for their ability to monitor early response to treatment with a novel MDM2 inhibitor. Methods: 2’-Deoxy-2’-18F-fluoro-D-glucose (FDG) is used to measure glucose transport and hexokinase activity, and its use in cancer detection and response is based on the preferential glycolytic metabolism of tumor cells. 3′-Deoxy-3′-18F-fluoro-L-thymidine (FLT), an analog of thymidine, can measure nucleoside transport and thymidine kinase activity, which is upregulated in the S-phase of mitosis and can serve as a surrogate for cellular proliferation. Two p53WT in vivo tumor models were evaluated: (1) MDM2-amplified SJSA-1 human osteosarcoma xenografts which exhibit tumor regression upon MDM2 inhibitor treatment, and (2) MDM2-WT HCT116 human colon carcinoma xenografts which exhibit tumor stasis upon treatment. FDG and FLT PET scans (separate cohorts) were acquired (1) 24 hr before treatment with MDM2 inhibitor or vehicle (i.e., baseline), (2) after 6 hr and 72 hr of treatment, and (3) 72 hr after cessation of treatment (i.e., wash-out). Results: MDM2 inhibitor treatment resulted in comparable decreases in FDG and FLT tumor standardized uptake values (SUV) in SJSA-1 tumor xenografts at 6 hr post-treatment (-23% and -9% relative to baseline, respectively; P<0.01) that persisted throughout the 72 hr treatment (-52% and -34%, respectively; P<0.001) and 72 h wash-out period (-54%; P<0.0005 and -28%, respectively). In HCT116 xenografts, MDM2 inhibitor treatment significantly reduced FLT tumor SUV at 6 hr post-treatment (-32% relative to baseline, P<0.005) and persisted throughout the 72 hr treatment (-70%; P<0.001), and rebounded sharply by the end of the wash-out period in HCT116 xenografts (-32%; P<0.005). FDG tumor SUV was not significantly reduced at any timepoint in HCT116 xenografts. Conclusions: FDG and FLT PET imaging were roughly equivalent in ability to monitor efficacy of MDM2 inhibitor treatment in a SJSA-1 tumor regression model; however only FLT PET imaging revealed a treatment effect in the HCT116 tumor stasis model. FLT PET imaging was successfully used as a noninvasive tool to provide quantitative measurement of tumor response to treatment with a novel MDM2 inhibitor. These results suggest that FLT PET imaging could have utility as an early clinical pharmacodynamic biomarker. Citation Format: Tim Kazules, Becky Bryant, Matt Silva, Jude Canon, Charles Glaus. 18F-FLT PET imaging for noninvasive, early assessment of tumor response to MDM2-p53 disruption using a novel MDM2 inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2658. doi:10.1158/1538-7445.AM2013-2658