Automated radiosynthesis of [11 C]MTP38-a phosphodiesterase 7 imaging tracer-using [11 C]hydrogen cyanide for clinical applications.

We have developed 8-amino-3-(2S,5R-dimethyl-1-piperidyl)-[1,2,4]triazolo[4,3-a]pyrazine-5-[11 C]carbonitrile ([11 C]MTP38) as a positron emission tomography (PET) tracer for the imaging of phosphodiesterase 7. For the fully automated production of [11 C]MTP38 routinely and efficiently for clinical applications, we determined the radiosynthesis procedure of [11 C]MTP38 using [11 C]hydrogen cyanide ([11 C]HCN) as a PET radiopharmaceutical. Radiosynthesis of [11 C]MTP38 was performed using an automated 11 C-labeling synthesizer developed in-house within 40 min after the end of irradiation. [11 C]MTP38 was obtained with a relatively high radiochemical yield (33 ± 5.5% based on [11 C]CO2 at the end of irradiation, decay-corrected, n = 15), radiochemical purity (>97%, n = 15), and molar activity (47 ± 12 GBq/µmol at the end of synthesis, n = 15). All the results of the quality control (QC) testing for the [11 C]MTP38 injection complied with our in-house QC and quality assurance specifications. We successfully automated the radiosynthesis of [11 C]MTP38 for clinical applications using an 11 C-labeling synthesizer and sterile isolator. Taken together, this protocol provides a new radiopharmaceutical [11 C]MTP38 suitable for clinical applications.

Synthesis and preclinical evaluation of [11C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain.

PURPOSE: Phosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [11C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7. METHODS: [11C]MTP38 was radiosynthesized by 11C-cyanation of a bromo precursor with [11C]HCN. PET scans of rat and rhesus monkey brains and in vitro autoradiography of brain sections derived from these species were conducted with [11C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (VT). The non-displaceable binding potential (BPND) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BPND. RESULTS: [11C]MTP38 was synthesized with radiochemical purity ≥99.4% and molar activity of 38.6 ± 12.6 GBq/µmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated VT values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm3, respectively. The cerebellar VT value was unchanged by pretreatment with unlabeled MTP38. Striatal BPND was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill's sigmoidal function. CONCLUSION: We have provided the first successful preclinical demonstration of in vivo PDE7 imaging with a specific PET radioligand. [11C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.

Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety.

We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-á-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.

Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor.

Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.

Total synthesis of (-)-FR182877 through tandem IMDA-IMHDA reactions and stereoselective transition-metal-mediated transformations.

Intelligent design: The total synthesis of the cytotoxic (-)-FR182877 relies on 1) tandem Diels-Alder reactions to close rings A-D (see scheme), 2) a palladium-mediated 7-exo-trig reaction, and 3) an iridium-mediated isomerization followed by epimerization and stereoselective reduction.

Quetiapine-induced neuroleptic malignant syndrome in dementia with Lewy bodies: a case report.

Patients with dementia with Lewy bodies (DLB) are particularly vulnerable to adverse effects of neuroleptics; this sensitivity is included among the clinical diagnostic criteria for DLB. Recently atypical neuroleptics, which carry less risk of extrapyramidal side effects than typical agents, have come into increasing use in treating psychotic symptoms and behavioral disturbances related to DLB. The present report is the first to describe a DLB patient who developed neuroleptic malignant syndrome (NMS) induced by quetiapine, an atypical neuroleptic known to have relatively infrequent extrapyramidal side effects in DLB patients. Physicians should be aware of the possibility of the occurrence of NMS in DLB even when atypical neuroleptics are administered.

Lack of association in Japanese patients between neuroleptic malignant syndrome and the TaqI A polymorphism of the dopamine D2 receptor gene.

OBJECTIVE: The molecular basis of neuroleptic malignant syndrome (NMS) is unclear, but clinical studies have noted a genetic predisposition. A recent genetic study suggested an association between NMS and the I A polymorphism in the dopamine D2 receptor (DRD2 ) gene. We further examined the association in a larger number of subjects. METHODS: We studied 49 Japanese patients previously diagnosed with NMS, and 123 schizophrenic patients treated with neuroleptics without occurrence of NMS. PCR and RFLP analyses were performed to screen the I A polymorphism. RESULTS: The I A1 allele frequency was 0.408 in NMS patients and 0.415 in patients without NMS. No significant differences in allelic or genotypic frequencies were observed between the two groups. CONCLUSIONS: We cannot conclude that the I A polymorphism is associated with development of NMS.

[A Japanese family with familial Alzheimer's disease associated with presenilin 1 mutation: relationship between younger age of onset and ApoE gene polymorphism].

We previously reported a Japanese family with early-onset familial Alzheimer's disease associated with G 209 R presenilin 1(PS 1) mutation. There have been six patients across three generations in this family. In the present report, we described the clinical course, findings with neuroimaging and results of genetic examination of PS 1 and apolipoprotein E(ApoE) in three of six patients(II-1, III-1 and 2). The clinical course was common to all three patients. Memory disturbance, disorientation, amnestic aphasia, personality changes and perseveration appeared at early stages, whereas Gerstmann's syndrome, myoclonus and general convulsion were recognized at advanced stages. CT disclosed mild brain atrophy in the temporal lobes at early stages and diffuse brain atrophy predominantly in the fronto--temporal lobes at advanced stages. SPECT exhibited hypoperfusion in the fronto-temporal areas at early stages and hypoperfusion in the fronto-temporal and parieto-occipital areas at advanced stages. The age of onset in six patients demonstrated two clusters at age 53-55(I-1, II-1, 2 and 5) and age 46-48(III-1 and 2). PS 1 genotyping demonstrated that the heterozygous exonic missense mutation G 209 R was confirmed in all three patients. Regarding the ApoE genotyping, II-1(mother) was epsilon 3/epsilon 3, whereas III-1 and 2(children) were epsilon 3/epsilon 4. These findings suggest the possibility that there might be a gene dose effect, since the age of onset ranged from 5 to 7 years younger in patients who received epsilon 4 alleles from the father.

Anxiety and prevalence of psychiatric disorders among patients awaiting surgery for suspected ovarian cancer.

AIM: The goal of the current study was to determine the anxiety level and prevalence of psychiatric disorders among patients awaiting surgery for ovarian tumors. Also analyzed were the predictive factors for psychiatric disorders and changes after surgical diagnosis. METHODS: Patients who underwent surgery for ovarian tumors were examined before and after surgery with the MINI International Neuropsychiatric Interview, the Spielberger State-Trait Anxiety Inventory (STAI) and the Mausley Personality Inventory (MPI). Participants diagnosed with cancer were examined a third time after being given an explanation about whether or not adjuvant chemotherapy was required. RESULTS: Twenty-seven participants completed the study and were analyzed. Nine (33.3%) of these 27 participants were diagnosed as having adjustment disorder. There were no differences in the demographic data, STAI trait anxiety score and MPI score between the participants with or without adjustment disorder. At the pre-surgical interview, the STAI state anxiety score of the participants was high (49.5 +/- 10.30). After pathological examination of the tumors, it was found that 12 patients had cancer (malignant group) and 15 patients had a benign tumor (benign group). At pre-surgery, the prevalence of adjustment disorder and the level of anxiety in the benign group were similar to those in the malignant group. There was a second surge of anxiety in patients who needed chemotherapy. CONCLUSION: The above findings demonstrate that patients with suspected ovarian cancer experience a high level of anxiety. Physicians should be aware of the risk of adjustment disorder in these patients. Additionally, ovarian cancer patients need psychological assessment during the course of treatment.

CYP2D6 gene deletion allele in patients with neuroleptic malignant syndrome: preliminary report.

Neuroleptic malignant syndrome (NMS) is a potentially fatal adverse reaction to psychopharmacologic treatment. Reported herein are two NMS patients with schizophrenia who were found to possess a CYP2D6 gene deletion allele (CYP2D6*5). The deletion results in decreased CYP2D6 activity, possibly leading to drug accumulation. Both patients with NMS had been treated with neuroleptics, including CYP2D6 substrates. Polymerase chain reaction (PCR) followed by restriction fragment length polymorphism analyses and long PCR were performed to detect CYP2D6 genotype. One patient was found to possess *5/*10; the other had a *1/*5 genotype. The present preliminary report suggests that pharmacokinetic factors cannot be excluded and the CYP2D6 polymorphism is possibly associated with the etiology of NMS.

Asymmetric catalysis on the intramolecular cyclopropanation of alpha-diazo-beta-keto sulfones.

This work describes the development of a highly enantioselective asymmetric catalysis on the intramolecular cyclopropanation of alpha-diazo-beta-keto sulfones. We have found that the catalytic asymmetric intramolecular reactions of alpha-diazo-beta-keto sulfones generally proceed with high enantioselectivity when the alpha-diazo-beta-keto mesityl sulfone is used with the newly prepared ligand 2e. The absolute configuration of products has been determined by X-ray crystallographic analysis, and the outcome of the enantioselectivities is explained well by our proposed models A and B. The products possess great potential for natural product synthesis because (1) many different chemistries of cyclopropane, ketone, and sulfone are available, and (2) the products are generally highly crystalline, facilitating the supplies of enantiomerically pure synthetic intermediates.