Erythropoietin (EPO) is a tissue-protective cytokine preventing vascular spasm, apoptosis, and inflammatory responses. Although best known for its role in hematopoietic lineages, EPO also affects other tissues, including those of the nervous system. Enthusiasm for recombinant human erythropoietin (rhEPO) as a potential neuroprotective therapeutic must be tempered, however, by the knowledge it also enlarges circulating red cell mass and increases platelet aggregability. Here we examined whether erythropoietic and tissue-protective activities of rhEPO might be dissociated by a variation of the molecule. We demonstrate that asialoerythropoietin (asialoEPO), generated by total enzymatic desialylation of rhEPO, possesses a very short plasma half-life and is fully neuroprotective. In marked contrast with rhEPO, this molecule at doses and frequencies at which rhEPO exhibited erythropoiesis, did not increase the hematocrit of mice or rats. AsialoEPO appeared promptly within the cerebrospinal fluid after i.v. administration; intravenously administered radioiodine-labeled asialoEPO bound to neurons within the hippocampus and cortex in a pattern corresponding to the distribution of the EPO receptor. Most importantly, asialoEPO exhibits a broad spectrum of neuroprotective activities, as demonstrated in models of cerebral ischemia, spinal cord compression, and sciatic nerve crush. These data suggest that nonerythropoietic variants of rhEPO can cross the blood–brain barrier and provide neuroprotection.

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Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-11 C-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo [1,5-a]pyridine ( 11 C-Lu AE92686) and its tritiated analog 3 H-Lu AE92686. Methods: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and 11 C-labeled compounds were synthesized. 3 H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and 11 C-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. Results: 11 C-Lu AE92686 displayed high specificity and selectivity for PDE10A-expressing regions in the brain of cynomolgus monkeys and humans. Similar results were found in rodents using 3 H-Lu AE92686. The binding of 11 C-Lu AE92686 and 3 H-Lu AE92686 to striatum was completely and dose-dependently blocked by the structurally different PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (MP-10) in rodents and in monkeys. In all species, specific binding of the radioligand was seen in the striatum but not in the cerebellum, supporting the use of the cerebellum as a reference region. The binding potentials (BP ND ) of 11 C-Lu AE92686 in the striatum of both cynomolgus monkeys and humans were evaluated by the simplified reference tissue model with the cerebellum as the reference tissue, and BP ND was found to be high and reproducible-that is, BP ND s were 6.5 ± 0.3 (n 5 3) and 7.5 ± 1.0 (n 5 12) in monkeys and humans, respectively. Conclusion: Rodent, monkey, and human tests of labeled Lu AE92686 suggest that 11 C-Lu AE92686 has great potential as a human PET tracer for the PDE10A enzyme.Key Words: 11 C; 3 H; PET; PDE10A; brain imaging; Lu AE92686 J Nucl Med 2014; 55:1513 55: -1518 55: DOI: 10.2967 Phosphodi esterase 10A (PDE10A) is predominantly expressed in medium spiny neurons and plays a key role in striatal signaling. During the past 10 y, large efforts have been made to develop PDE10A inhibitors for the treatment of schizophrenia (1-3). Preclinical evidence in several animal models suggests that PDE10A inhibitors can improve positive, negative, and cognitive symptoms of schizophrenia, and current clinical trials evaluate PDE10A inhibitors for the treatment of schizophrenia (4). Noninvasive imaging techniques such as PET may be useful for the clinical development of PDE10A inhibitors, because they may provide comparative data on the expression of the enzyme in healthy individuals and in individuals with brain disorders. Furthermore, a PDE10A PET ligand can be used to provide evidence that a clinical drug candidate reaches and bind...