Robust Quantification of Phosphodiesterase-4D in Monkey Brain with PET and 11C-Labeled Radioligands That Avoid Radiometabolite Contamination.

Phosphodiesterase-4D (PDE4D) has emerged as a significant target for treating neuropsychiatric disorders, but no PET radioligand currently exists for robustly quantifying human brain PDE4D to assist biomedical research and drug discovery. A prior candidate PDE4D PET radioligand, namely [11C]T1650, failed in humans because of poor time stability of brain PDE4D-specific signal (indexed by total volume of distribution), likely due to radiometabolites accumulating in brain. Its nitro group was considered to be a source of the brain radiometabolites. Methods: We selected 5 high-affinity and selective PDE4D inhibitors, absent of a nitro group, from our prior structure-activity relationship study for evaluation as PET radioligands. Results: All 5 radioligands were labeled with 11C (half-time, 20.4 min) in useful yields and with high molar activity. All displayed sizable PDE4D-specific signals in rhesus monkey brain. Notably, [11C]JMJ-81 and [11C]JMJ-129 exhibited excellent time stability of signal (total volume of distribution). Furthermore, as an example, [11C]JMJ-81 was found to be free of radiometabolites in ex vivo monkey brain, affirming that this radioligand can provide robust quantification of brain PDE4D with PET. Conclusion: Given their high similarity in structures and metabolic profiles, both [11C]JMJ-81 and [11C]JMJ-129 warrant further evaluation in human subjects. [11C]JMJ-129 shows a higher PDE4D specific-to-nonspecific binding ratio and will be the first to be evaluated.

Gadolinium-labeled affibody-XTEN recombinant vector for detection of HER2+ lesions of ovarian cancer lung metastasis using quantitative MRI.

Ovarian cancer has the highest mortality rate among all gynecologic malignancies. HER2+ ovarian cancer is a subtype that is aggressive and associated with metastasis to distant sites such as the lungs. Therefore, accurate biological characterization of metastatic lesions is vital as it helps physicians select the most effective treatment strategy. Functional imaging of ovarian cancer with PET/CT is routinely used in the clinic to detect metastatic disease and evaluate treatment response. However, this imaging method does not provide information regarding the presence or absence of cancer-specific cell surface biomarkers such as HER2. As a result, this method does not help physicians decide whether to choose immunotherapy to treat metastasis. To differentiate the HER2+ from HER2¯ lesions in ovarian cancer lung metastasis, AbX50C4:Gd vector composed of a HER2 targeting affibody and XTEN peptide was genetically engineered. It was then labeled with gadolinium (Gd) via a stable linker. The vector was characterized physicochemically and biologically to determine its purity, molecular weight, hydrodynamic size and surface charge, stability in serum, endotoxin levels, relaxivity and ability to target the HER2 antigen. Then, SCID mice were implanted with SKOV-3 (HER2+) and OVASC-1 (HER2¯) tumors in the lungs and injected with the Gd-labeled HER2 targeted AbX50C4:Gd vector. The mice were imaged using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), followed by R1-mapping and quantitative analysis of the images. Our data demonstrate that the developed HER2-targeted vector can differentiate HER2+ lung metastasis from HER2¯ lesions using DCE-MRI. The developed vector could potentially be used in conjunction with other imaging modalities to prescreen patients and identify candidates for immunotherapy while triaging those who may not be considered responsive.

(18)F-DPA-714 PET Imaging for Detecting Neuroinflammation in Rats with Chronic Hepatic Encephalopathy.

Neuroinflammation is considered to be the pathogenesis of hepatic encephalopathy (HE), and imaging neuroinflammation is implicated in HE management. (11)C-PK11195, a typical translocator protein (TSPO) radiotracer, is used for imaging neuroinflammation. However, it has inherent limitations, such as short half-life and limited availability. The purpose of this study was to demonstrate the efficiency of new generation TSPO radiotracer, (18)F-DPA-714, in detecting and monitoring neuroinflammation of chronic HE. This study was divided into two parts. The first part compared (18)F-DPA-714 and (11)C-PK11195 radiotracers in ten HE induced rats [bile duct ligation (BDL) and fed hyperammonemic diet (HD)] and 6 control rats. The animal subjects underwent dynamic positron emission tomography (PET) during 2-day intervals. The (11)C-PK11195 PET study showed no differences in whole brain average percent injected dose per gram (%ID/g) values at all time points (all P>0.05), while the (18)F-DPA-714 PET study showed higher whole brain average %ID/g values in HE rats compared to control group rats at 900 s to 3300 s after injecting radiotracer (all P<0.05). The second part of the study evaluated the effectiveness of ibuprofen (IBU) treatment to chronic HE. Forty rats were classified into six groups, including Sham+normal saline (NS), Sham+IBU, BDL+NS, BDL+HD+NS, BDL+IBU, and BDL+HD+IBU groups. (18)F-DPA-714 PET was used to image neuroinflammation. Whole and regional brain average %ID/g values, neurological features, inflammatory factors and activated microglia showed better in the IBU groups than in the NS groups (all P<0.05) and no difference was seen in the Sham groups compared to IBU groups (all P>0.05). In conclusion, this study demonstrated that (18)F-DPA-714 is an ideal TPSO radiotracer for imaging neuroinflammation and monitoring anti-neuroinflammation treatment efficacy of chronic HE.

PET and MR imaging of neuroinflammation in hepatic encephalopathy.

Neurological or psychiatric abnormalities associated with hepatic encephalopathy (HE) range from subclinical findings to coma. HE is commonly accompanied with the accumulation of toxic substances in bloodstream. The toxicity effect of hyperammonemia on astrocyte, such as the alteration in neurotransmission, oxidative stress, astrocyte swelling, is considered as an important factor in the pathogenesis of HE. Besides, neuroinflammation has captured more attention in the process of HE, but the mechanism of neuroinflammation leading to HE remains unclear. Molecular imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) targeting activated microglia and/ or other mediators appear to be promising noninvasive approaches to assess HE. This review focuses on novel imaging and therapy strategies of neuroinflammation in HE.