A comparison of 64Cu-labeled bi-terminally PEGylated A20FMDV2 peptides targeting integrin ανβ6

Expression of epithelial-specific integrin

Three-Dimensional Dose Model for the Comparison of 177Lu-HuCC49ΔCH2 and 177Lu-HuCC49 Radioimunotherapy in Mice Bearing Intraperitoneal Xenografts

Uptake and dose distributions in peritoneal LS174T colon tumor xenografts were compared for a humanized construct of the CC49 (HuCC49) high-affinity anti-TAG-72 monoclonal antibody and a construct with the CH2 region deleted (HuCC49ΔCH2), both labeled with 177Lu using a PA-DOTA bifunctional chelating agent and injected in the peritoneum. Tumors were resected and serially sectioned at 1 h, 4 h, 24 h, and 48 h postinjection. Between 5 and 24 (average 16) sections were retained per tumor for autoradiography. The typical section interval was 340 μm and thickness was 16 μm. Tumor sections were air dried and placed on film and/or phosphor screen. Section images were digitized at 100 μm resolution electronically (phosphor screen) or by laser densitometer (film). Section images were used to generate tumor surface descriptions and activity distributions by reconstructing the activity densities in three dimensions. Three-dimensional dose-rate calculations, performed using a point kernel for 177Lu, were used to prepare radial histograms describing the variation in dose rate as a function of distance from the tumor center to surface. At early times postinjection, the 177Lu-HuCC49ΔCH2 antibody displayed higher dose rates near the tumor surface compared to the 177Lu-HuCC49 antibody. At 24 h postinjection, dose rate distributions appeared similar for both antibodies and more uniform than at earlier times. The 177Lu-HuCC49ΔCH2 antibody indicated improved uniformity at 48 h postinjection. Cell survival calculations based on the three-dimensional dose rate distributions favored 177Lu-HuCC49ΔCH2 for equal injection activities. However the most significant effect was the greater injected dose tolerated for the 177Lu-HuCC49ΔCH2 antibody based on equivalent estimated bone marrow dose.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63413/1/108497803765036418.pd

Preclinical efficacy of a PARP-1 targeted Auger-emitting radionuclide in prostate cancer

There is an unmet need for better therapeutic strategies for advanced prostate cancer. Poly (ADP-ribose) polymerase-1 (PARP-1) is a chromatin-binding DNA repair enzyme overexpressed in prostate cancer. This study evaluates whether PARP-1, on account of its proximity to the cell\u27s DNA, would be a good target for delivering high-linear energy transfer Auger radiation to induce lethal DNA damage in prostate cancer cells. We analyzed the correlation between PARP-1 expression and Gleason score in a prostate cancer tissue microarray. A radio-brominated Auger emitting inhibitor (

Radiosynthesis and evaluation of talazoparib and its derivatives as PARP-1-targeting agents

Poly (ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme in the DNA repair process and the target of several FDA-approved inhibitors. Several of these inhibitors have been radiolabeled for non-invasive imaging of PARP-1 expression or targeted radiotherapy of PARP-1 expressing tumors. In particular, derivatives of olaparib and rucaparib, which have reduced trapping potency by PARP-1 compared to talazoparib, have been radiolabeled for these purposes. Here, we report the first radiosynthesis of

Radiolabeled 6-(2, 3-dichlorophenyl)-N4-methylpyrimidine-2, 4-diamine (TH287): A potential radiotracer for measuring and imaging MTH1

MTH1 (MutT homolog 1) or NUDT1 (Nudix Hydrolase 1), also known as oxidized purine nucleoside triphosphatase, has potential as a biomarker for monitoring cancer progression and quantifying target engagement for relevant therapies. In this study, we validate one MTH1 inhibitor TH287 as a PET MTH1 radiotracer. TH287 was radiolabeled with tritium and the binding of

Novel chelating agents for zirconium-89-positron emission tomography (PET) imaging: Synthesis, DFT calculation, radiolabeling, and in vitro and in vivo complex stability

We report the synthesis and evaluation of novel chelating agents for zirconium-89

Cross-inhibition of NMBR and GRPR signaling maintains normal histaminergic itch transmission

We previously showed that gastrin-releasing peptide receptor (GRPR) in the spinal cord is important for mediating nonhistaminergic itch. Neuromedin B receptor (NMBR), the second member of the mammalian bombesin receptor family, is expressed in a largely nonoverlapping pattern with GRPR in the superficial spinal cord, and its role in itch transmission remains unclear. Here, we report that Nmbr knock-out (KO) mice exhibited normal scratching behavior in response to intradermal injection of pruritogens. However, mice lacking both Nmbr and Grpr (DKO mice) showed significant deficits in histaminergic itch. In contrast, the chloroquine (CQ)-evoked scratching behavior of DKO mice is not further reduced compared with Grpr KO mice. These results suggest that NMBR and GRPR could compensate for the loss of each other to maintain normal histamine-evoked itch, whereas GRPR is exclusively required for CQ-evoked scratching behavior. Interestingly, GRPR activity is enhanced in Nmbr KO mice despite the lack of upregulation of Grpr expression; so is NMBR in Grpr KO mice. We found that NMB acts exclusively through NMBR for itch transmission, whereas GRP can signal through both receptors, albeit to NMBR to a much lesser extent. Although NMBR and NMBR(+) neurons are dispensable for histaminergic itch, GRPR(+) neurons are likely to act downstream of NMBR(+) neurons to integrate NMB-NMBR-encoded histaminergic itch information in normal physiological conditions. Together, we define the respective function of NMBR and GRPR in itch transmission, and reveal an unexpected relationship not only between the two receptors but also between the two populations of interneurons in itch signaling