Study of The \u3cem\u3eN\u3c/em\u3e = 77 Isotones Near The Proton-drip Line; Isomeric Decays of \u3csup\u3e140\u3c/sup\u3eEu, \u3csup\u3e142\u3c/sup\u3eTb, \u3csup\u3e144\u3c/sup\u3eHo, and \u3csup\u3e146\u3c/sup\u3eTm

In this dissertation, the systematics of the [pi]h₁₁/₂ [tensor] [nu]h₁₁/₂ and [pi]h₁₁/₂ [tensor] [nu]s₁/₂ isomeric configurations were studied for the odd-Z, N = 77 isotones near the proton drip line. The isomeric decays in ¹⁴⁰Eu, ¹⁴²Tb, ¹⁴⁴Ho and ¹⁴⁶Tm were measured by means of X-ray, [gamma]-ray and charged particle spectroscopy at the Recoil Mass Spectrometer at the Holifield Radioactive Ion Beam Facility (HRIBF) at Oak Ridge National Laboratory (ORNL). The spin and parity of I[pi] = 8⁺ and 5⁻ were deduced for the isomers in ¹⁴⁰ Eu and ¹⁴²Tb. New decay schemes were established, and the half-lives of the 8⁺ isomers were measured to be 302(3) ns for ¹⁴⁰m²Eu and 25(1) [mu]s for ¹⁴²m²Tb. No evidence for the expected 1⁺ ground-state was found in the ¹⁴⁴Ho decay data. The proton emission from ¹⁴⁶Tm was restudied. Five proton transitions were assigned to two proton emitting states. The half-lives of 198(3) ms and 68(3) ms and the spin and parity values of I[pi] = 10⁺ and 5⁻ were established for ¹⁴⁶mTm and ¹⁴⁶gsTm, respectively. For the first time for an odd-odd nucleus, the interpretation of the observed decay properties and structure of the proton-emitting states was made by accounting the deformation and proton and neutron coupling to the core excitations. A complex wave function structure was obtained, with dominating components of [pi]h₁₁/₂ [tensor] [nu]h₁₁/₂ for the10⁺ isomer and [pi]h₁₁/₂ [tensor] [nu]s₁/₂ for the 5⁻ ground state. Details of the experimental setup and results as well as a brief description of the detectors used in the experiments and the HRIBF facility will be discussed in this dissertation

Feasibility of [18F]FSPG PET for Early Response Assessment to Combined Blockade of EGFR and Glutamine Metabolism in Wild-Type KRAS Colorectal Cancer

Early response assessment is critical for personalizing cancer therapy. Emerging therapeutic regimens with encouraging results in the wild-type (WT) KRAS colorectal cancer (CRC) setting include inhibitors of epidermal growth factor receptor (EGFR) and glutaminolysis. Towards predicting clinical outcome, this preclinical study evaluated non-invasive positron emission tomography (PET) with (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) in treatment-sensitive and treatment-resistant WT KRAS CRC patient-derived xenografts (PDXs). Tumor-bearing mice were imaged with [18F]FSPG PET before and one week following the initiation of treatment with either EGFR-targeted monoclonal antibody (mAb) therapy, glutaminase inhibitor therapy, or the combination. Imaging was correlated with tumor volume and histology. In PDX that responded to therapy, [18F]FSPG PET was significantly decreased from baseline at 1-week post-therapy, prior to changes in tumor volume. In contrast, [18F]FSPG PET was not decreased in non-responding PDX. These data suggest that [18F]FSPG PET may serve as an early metric of response to EGFR and glutaminase inhibition in the WT KRAS CRC setting

Simplified [F]FDG Image-Derived Input Function Using the Left Ventricle, Liver, and One Venous Blood Sample

A relatively simple, almost entirely noninvasive imaging-based method is presented for deriving arterial blood input functions for quantitative [ 18 F]2-fluoro-2-deoxy- d -glucose (FDG) positron emission tomographic (PET) studies in rodents. It requires only one venous blood sample at the end of the scan. MicroPET images and arterial blood time-activity curves (TACs) were downloaded from the Mouse Quantitation Program database at the University of California, Los Angeles. Three-dimensional regions of interest were drawn around the blood-pool region of the left ventricle and within the liver to derive their respective TACs. To construct the “hybrid” image-derived input function (IDIF), the initial part of the left ventricle TAC, containing the peak concentration of [ 18 F]FDG in the arterial blood, was corrected for spillout (ie, partial-volume effect yielding a recovery coefficient < 1) and then joined to the liver TAC (normalized to the 60-minute arterial blood sample) immediately after it peaks. To validate our method, the [ 18 F]FDG influx constant (K i ) was estimated using a two-tissue compartment model and compared to estimates of K i obtained using measured arterial blood TACs. No significant difference in the K i estimates was obtained with the arterial blood input function and our hybrid IDIF. We conclude that the normalized hybrid IDIF can be used in practice to obtain reliable K i estimates

TSPO-targeted PET and Optical Probes for the Detection and Localization of Premalignant and Malignant Pancreatic Lesions

Pancreatic cancer is among the most aggressive malignancies and is rarely discovered early. However, pancreatic "incidentalomas," particularly cysts, are frequently identified in asymptomatic patients through anatomic imaging for unrelated causes. Accurate determination of the malignant potential of cystic lesions could lead to life-saving surgery or spare patients with indolent disease undue risk. Current risk assessment of pancreatic cysts requires invasive sampling, with attendant morbidity and sampling errors. Here, we sought to identify imaging biomarkers of high-risk pancreatic cancer precursor lesions. Translocator protein (TSPO) expression, which is associated with cholesterol metabolism, was evaluated in premalignant and pancreatic cancer lesions from human and genetically engineered mouse (GEM) tissues. imaging was performed with [ F]V-1008, a TSPO-targeted PET agent, in two GEM models. For image-guided surgery (IGS), V-1520, a TSPO ligand for near-IR optical imaging based upon the V-1008 pharmacophore, was developed and evaluated. TSPO was highly expressed in human and murine pancreatic cancer. Notably, TSPO expression was associated with high-grade, premalignant intraductal papillary mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasia (PanIN) lesions. In GEM models, [ F]V-1008 exhibited robust uptake in early pancreatic cancer, detectable by PET. Furthermore, V-1520 localized to premalignant pancreatic lesions and advanced tumors enabling real-time IGS. We anticipate that combined TSPO PET/IGS represents a translational approach for precision pancreatic cancer care through discrimination of high-risk indeterminate lesions and actionable surgery

Molecular Imaging of Therapeutic Response to Epidermal Growth Factor Receptor Blockade in Colorectal Cancer

PURPOSE: To evaluate noninvasive molecular imaging methods as correlative biomarkers of therapeutic efficacy of cetuximab in human colorectal cancer cell line xenografts grown in athymic nude mice. The correlation between molecular imaging and immunohistochemical analysis to quantify epidermal growth factor (EGF) binding, apoptosis, and proliferation was evaluated in treated and untreated tumor-bearing cohorts. EXPERIMENTAL DESIGN: Optical imaging probes targeting EGF receptor (EGFR) expression (NIR800-EGF) and apoptosis (NIR700-Annexin V) were synthesized and evaluated in vitro and in vivo. Proliferation was assessed by 3′-[(18)F]fluoro-3′-deoxythymidine ([(18)F] FLT) positron emission tomography. Assessment of inhibition of EGFR signaling by cetuximab was accomplished by concomitant imaging of NIR800-EGF, NIR700-Annexin V, and [(18)F] FLT in cetuximab-sensitive (DiFi) and insensitive (HCT-116) human colorectal cancer cell line xenografts. Imaging results were validated by measurement of tumor size and immunohistochemical analysis of total and phosphorylated EGFR, caspase-3, and Ki-67 immediately following in vivo imaging. RESULTS: NIR800-EGF accumulation in tumors reflected relative EGFR expression and EGFR occupancy by cetuximab. NIR700-Annexin V accumulation correlated with cetuximab-induced apoptosis as assessed by immunohistochemical staining of caspase-3. No significant difference in tumor proliferation was noted between treated and untreated animals by [(18)F] FLT positron emission tomography or Ki-67 immunohistochemistry. CONCLUSIONS: Molecular imaging can accurately assess EGF binding, proliferation, and apoptosis in human colorectal cancer xenografts. These imaging approaches may prove useful for serial, noninvasive monitoring of the biological effects of EGFR inhibition in preclinical studies. It is anticipated that these assays can be adapted for clinical use