The elevation of kynurenic acid (KYNA) observed in schizophrenic patients may contribute to core symptoms arising from glutamate hypofunction, including cognitive impairments. Although increased KYNA levels reduce excitatory neurotransmission, KYNA has been proposed to act as an endogenous antagonist at the glycine site of the glutamate NMDA receptor (NMDAR) and as a negative allosteric modulator at the ␣7 nicotinic acetylcholine receptor. Levels of KYNA are elevated in CSF and the postmortem brain of schizophrenia patients, and these elevated levels of KYNA could contribute to NMDAR hypofunction and the cognitive deficits and negative symptoms associated with this disease. However, the impact of endogenously produced KYNA on brain function and behavior is less well understood due to a paucity of pharmacological tools. To address this issue, we identified PF-04859989, a brain-penetrable inhibitor of kynurenine aminotransferase II (KAT II), the enzyme responsible for most brain KYNA synthesis. In rats, systemic administration of PF-04859989 dose-dependently reduced brain KYNA to as little as 28% of basal levels, and prevented amphetamine-and ketamineinduced disruption of auditory gating and improved performance in a sustained attention task. It also prevented ketamine-induced disruption of performance in a working memory task and a spatial memory task in rodents and nonhuman primates, respectively. Together, these findings support the hypotheses that endogenous KYNA impacts cognitive function and that inhibition of KAT II, and consequent lowering of endogenous brain KYNA levels, improves cognitive performance under conditions considered relevant for schizophrenia.

No abstract

CE credit: For CE credit, you can access the test for this article, as well as additional JNMT CE tests, online at https://www.snmmilearningcenter.org. Complete the test online no later than September 2021. Your online test will be scored immediately. You may make 3 attempts to pass the test and must answer 80% of the questions correctly to receive 1.0 CEH (Continuing Education Hour) credit. SNMMI members will have their CEH credit added to their VOICE transcript automatically; nonmembers will be able to print out a CE certificate upon successfully completing the test. The online test is free to SNMMI members; nonmembers must pay $15.00 by credit card when logging onto the website to take the test. 177 Lu-DOTATATE is a radiolabeled somatostatin analog that has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors in adults. Radionuclide therapies have been administered for many years within nuclear medicine departments in North America. However, in comparison to other radiotherapies, 177 Lu-DOTATATE peptide receptor radionuclide therapy involves more planning, coordination, concomitant medication administration (antiemetic medications and amino acids), and direct patient care. To date, various methods have been used in multiple centers during the NETTER-1 trial and the provision of patient care. As participants in the phase 3 NETTER-1 trial and the subsequent expanded-access program for the administration of 177 Lu-DOTATATE studies, as well as recently starting postapproval clinical care, we have administered 61 177 Lu-DOTATATE therapies at the time of this manuscript submission (13 in the NETTER-1 trial, 39 in the expanded-access program, and 9 clinically) at the Dana-Farber Cancer Institute and here share our procedures, personnel training, and workflow to help other centers establish programs for this FDA-approved 177 Lu-DOTATATE peptide receptor radionuclide therapy.

◥Purpose: Most gastrointestinal stromal tumors (GIST) have activating mutations of KIT, PDGFRA, or uncommonly BRAF. Fifteen percent of adult and 85% of pediatric GISTs are wild type (WT), commonly having high expression of IGF-1R and loss of succinate dehydrogenase (SDH) complex function. We tested the efficacy of linsitinib, an oral TKI IGF-1R inhibitor, in patients with WT GIST.Patients and Methods: A multicenter phase II trial of linsitinib was conducted. The primary endpoint was objective response rate. Secondary endpoints were clinical benefit rate: complete response, partial response, and stable disease (SD) 9 months, and quantitative 2[18F]fluoro-2-deoxy-D-glucose (FDG) metabolic response (MR) at week 8. Serum levels for glucose, insulin, IGF-1R ligand IGF1, and binding proteins were obtained to explore correlations to patient outcomes and FDG-PET results.Results: Twenty patients were accrued in a 6-month period. Grade 3-4 toxicities possibly related to linsitinib were uncommon (8.5%). No objective responses were seen. Clinical benefit rate (CBR) at 9 months was 40%. Intense FDG uptake was observed at baseline, with partial MR of 12% and stable metabolic disease of 65% at week 8; these patients had RECIST 1.1 SD as their best response. Progression-free survival (PFS) and overall survival Kaplan-Meier estimates at 9 months were 52% and 80%, respectively. SDHA/B loss determined by IHC was seen in 35% and 88% of cases, respectively.Conclusions: Linsitinib is well tolerated in patients with WT GIST. Although the 9-month CBR was 40%, and PFS at 9 months was 52%, no objective responses were observed. Rapid accrual to this study demonstrates that clinical trials of experimental agents in selected subtypes of GIST are feasible.

Most breast cancers express androgen receptors (AR). This prospective imaging sub-study explored imaging AR with 18 F-fluoro-5α-dihydrotestosterone (FDHT)-PET in patients with metastatic breast cancer (MBC) receiving selective AR modulation (SARM) therapy (GTx-024).Methods: 11 post-menopausal women with estrogen receptor positive MBC underwent FDHT-PET/CT at baseline, 6, and 12 weeks after starting SARM therapy. Abnormal tumor FDHT uptake was quantified using maximum SUV (SUVmax). AR status was determined from tumor biopsy specimens. FDHT-SUVmax percent change between scans was calculated. Best overall response was categorized as clinical benefit (CB: non-progressive disease [PD]), or PD using RECIST 1.1).Results: Median baseline FDHT-SUVmax was 4.1 (range 1.4-5.9) for AR+ tumors versus 2.3 (range 1.5-3.2) for AR-tumors (p=0.22). Quantitative AR expression and baseline FDHT uptake were weakly correlated (Pearson rho=0.39, p=0.30). Seven participants with CB at 12 weeks tended to have larger declines in FDHT uptake compared to those with PD at both 6 (median decline, range: -26.8%, -42.9 to -14.1% vs. -3.7%, -31% to +29%, respectively, p=0.11) and 12 weeks (median decline, range: -35.7%, -69.5 to -7.7% vs. -20.1%, -26.6% to +56.5%, respectively, p=0.17) after starting GTx-024. Conclusion:This hypothesis-generating data suggests that FDHT-PET/CT is worth further study as an imaging biomarker for evaluating response of MBC to SARM therapy and reiterates the feasibility of including molecular imaging in multidisciplinary therapeutic trials.