Synthesis and Evaluation of 18F-INER-1577-3 as a Central Nervous System (CNS) Histone Deacetylase Imaging Agent.

BACKGROUND: Epigenetic dysfunction is implicated in many neurologic, psychiatric and oncologic diseases. Consequently, histone deacetylases (HDACs) inhibitors have been developed as therapeutic and imaging agents for these diseases. However, only a few radiotracers have been developed as HDACs imaging agents for the central nervous system (CNS). We report herein the synthesis and evaluation of [18F]INER-1577-3 ([18F]5) as an HDACs imaging agent for CNS. METHODS: [18F]INER-1577-3 ([18F]5) was synthesized by two methods: one-step (A) and two-step (B) methods. Briefly, radiofluorination of the corresponding precursors (11, 12) with K[18F]/K2.2.2 followed by purifications with HPLC gave ([18F]5). The quality of [18F]INER- 1577-3 synthesized by these methods was verified by HPLC and TLC as compared to an authentic sample. The inhibitions of [18F]INER-1577-3 and related HDACs inhibitors on tumor cells growth were carried out with breast cancer cell line 4T1 and MCF-7. The whole-body and brain uptake of [18F]INER-1577-3 in rats and AD mice were determined using a micro-PET scanner and the data was analyzed using PMOD. RESULTS: The radiochemical yield of [18F]INER-1577-3 synthesized by these two methods was 1.4 % (Method A) and 8.8% (Method B) (EOB), respectively. The synthesis time was 115 min and 100 min, respectively, from EOB. The inhibition studies showed that INER-1577-3 has a significant inhibitory effect in HDAC6 and HDAC8 but not HDAC2. PET studies in rats and AD mice showed a maximum at about 15 min postinjection for the whole brain of a rat (0.47 ± 0.03 %ID/g), SAMP8 mice (5.63 ± 1.09 %ID/g) and SAMR1 mice (7.23 ± 1.21 %ID/g). CONCLUSION: This study showed that INER-1577-3 can inhibit tumor cell growth and is one of a few HDACs inhibitors that can penetrate the blood-brain barrier (BBB) and monitor HDAC activities in AD mice. Thus, [18F]INER-1577-3 may be a potent HDACs imaging agent, especially for CNS.

Validity, reliability and responsiveness of a short version of the Stroke-Specific Quality of Life Scale in patients receiving rehabilitation.

OBJECTIVE: To examine the measurement properties of a short version of the Stroke-Specific Quality of Life Scale (SS-QoL-12). DESIGN: Self-report survey of patients with mild to moderate upper extremity dysfunction. PATIENTS: A total of 126 patients provided 252 observations before and after treatment. METHODS: The construct validity and reliability was examined using the Rasch model; the concurrent and predictive validity was estimated using Spearman's rank correlation coefficients. Paired t-test and the standardized response mean (SRM) were performed to estimate the responsiveness of the SS-QoL-12. RESULTS: The 2-factor model (psychosocial and physical domains) fit the data better with smaller deviances. All but 1 item showed acceptable fit, and no item biases were detected. The reliability of the subscales and the whole scale ranged from 0.67 to 0.99. The total score showed fair correlations with the criterion measures at pretreatment (ρ = 0.28-0.40) and fair to good correlations at post-treatment (ρ = 0.39-0.54). The subscales had low to fair correlations at pretreatment (ρ = 0.19-0.49) and fair to good correlations at post-treatment (ρ = 0.31-0.56). The total and the subscales had low to good predictions at baseline (ρ = 0.22-0.52). The whole scale and the psychosocial subscale were mildly responsive to change (SRM = 0.22), but the physical subscale was not responsive to change (SRM = 0.08). CONCLUSION: The SS-QoL-12 has acceptable to good measurement properties, with an advantage of requiring less time to administer than other scales. The use of the subscale and total scores depends on the purpose of research. Future studies should recruit stroke patients with a broad range of dysfunction and use a large sample size to validate the findings.

Assessing the streamlined Wolf motor function test as an outcome measure for stroke rehabilitation.

OBJECTIVE: This study investigates the clinimetric properties of the streamlined Wolf Motor Function Test (WMFT), a 6-item version of the performance time scale of the WMFT. METHODS: The streamlined WMFT, along with 2 criterion measures, the Fugl-Meyer Assessment (FMA) and the Stroke Impact Scale (SIS), were administered to 64 stroke patients before and after a 3-week intervention. Responsiveness was examined using the Wilcoxon signed rank test and standardized response mean (SRM). Criterion-related validity was investigated using the Spearman correlation coefficient (ρ). RESULTS: The mean score on the baseline FMA upper extremity of the patients was 44.84 (standard deviation = 12.77). The streamlined WMFT and the original performance time scale showed comparable responsiveness (SRM = 0.29 and 0.37, respectively). The concurrent validity of the streamlined WMFT was good (ρ = 0.57-0.69). For predictive validity, the streamlined WMFT showed slightly better association with the criterion measures (ρ = 0.60-0.68) than did the original scale (ρ = 0.56-0.64). CONCLUSIONS: Compared with the original scale, the streamlined WMFT showed improved clinical utility.