Introduction: Breast cancer is prevalent health issue in women. Currently PET scanning is used as a noninvasive means to provide physiological information the uptake of glucose and its metabolism. This is performed by using the 18F-FDG tracer, which is a glucose analog. Currently, in vitro experiments are executed to understand the metabolism and glucose uptake of breast cancer cell lines in order to develop novel therapeutics. However, the in vitro glucose uptake data on breast cancer cell lines contradicts our speculation of how the trend should look, which is based off our understanding of cell line's characteristics in human models. The aim of our study is to ensure if glucose uptake in vitro correlates with in vivo glucose uptake (FDG tracer).

Methods: 7 breast cancer cell lines were bilaterally implanted with the same cell line in the mammary fat pad of immunodeficient mice (SCID and NSG). The mice were monitored for volume growth and were imaged by microPET/CT when the tumors reached about 200 mm3. The mice were injected with about 200 μCi/0.1 ml concentrations.

Results and Discussions: Small correlation (R2 = 0.08394) was between the comparisons of glucose uptake in vitro and FDG uptake in vivo. Imaging was seen as inconsistent for two different cell lines. No correlation (R2 = 0.00666) was observed in the comparison between volume (in all instance) and their corresponding FDG uptake. Volume growth was an issue with all the animals and it is speculated that the implantation procedure is not optimal. Low correlation (R2 = 0.0352) is observed in the overall comparison between FDG uptakes and volume growth rate. A comparison was done to clarify if %ID/gmax can be used instead of SUVmax, which resulted in a strong correlation (as expected). Further studies are needed due to small sample size

Conclusion: At the end of the study, it was observed that glucose uptake in vitro does not correlate with FDG uptake in vivo. This has a strong implication that in vitro studies for glucose uptake might not be translated to in vivo uptake.

Targeted alpha therapy (TAT) is showing promise in the treatment of solid and liquid tumors. TAT uses alpha particles that have small effective range and high linear energy transfer (LET) to achieve high killing in tumor cells and spare normal tissues around the tumor cells. Currently, Actinium-225 (Ac-225) is the most sought-after alpha-emitter. To study the biodistribution of any Ac-225 labeled radiopharmaceuticals, we need to image Ac-225 in vivo in small animals at a sub-Ci activity level. With this research question, we investigate the feasibility of using a commercial preclinical single photon emission computed tomography scanner (SPECT) to quantitatively image a mouse-like phantom at low Ac-225 activity. We first developed an Ac-225 imaging protocol with the SPECT scanner. The protocol consisted of calibrating the scanner for two imageable photon emissions from the Ac-225 decay to Fr-221 and Bi-213 (218 keV and 440 keV). Then, we selected regions of interests (ROIs) from phantom images and characterized the quantitative accuracy of the resulting images as a function of activity in Ci equivalent to 1-hour exposure. For both energy windows, with three ROI methods, the recovery coefficients (RCs) showed consistent quantitative accuracy of SPECT images at an activity level as low as 3.36 Ci with 1-hour exposure. 20% or more deviation of RCs from the ground truth as well as increasing variations of RC values measured between phantom cavities were found at activities below 3.36 Ci. Additional phantom studies, at lower activity levels, and animal studies are being prepared for further investigation on the preclinical scanner’s limit of detection of Ac-225.

Systemic hypertension is a causative factor in left ventricular hypertrophy which has a range of co-morbidities. Pathologic hypertrophy may negatively impact essential cardiac function. Understanding the physical and biomechanical changes in the heart associated with hypertensive left ventricular hypertrophy is motivated by the potential to reverse or manage the dysfunction associated with structural remodeling of the myocardium in this pathology. Diffusion tensor imaging is a nondestructive magnetic resonance imaging technique that can be used to image myocardial tissue microstructure and determine the orientation of myocardial muscle fibers. In this study, we present an analysis of myocardial fiber and laminar sheet orientation using the covariance of the diffusion tensor to quantify changes in orientation associated with myocardial tissue remodeling. We performed an ex vivo evaluation of hypertrophic and normal rat hearts (N=11) using diffusion tensor magnetic resonance imaging. We observed that the hypertrophic myocardium exhibited significantly increased myocardial fiber derangement (p=0.033), having a mean dispersion of 40 degrees. In comparison, normotensive myocardium had a mean of 36 degrees of dispersion. The calculated dispersion of the laminar sheet normal in the wild-type population was 52 degrees, compared to 55 degrees in the hypertrophic population (p=0.056). The fiber orientation distribution and dispersion data we obtained could be used to further evaluate the biomechanics of myocardial hypertrophy.

Studies have shown that hypertension is associated with abnormalities of calcium metabolism, and it may lead to increase the risk of fractures and osteoporosis. However, several recent clinical findings in the past decade revealed an inverse correlation between bone mineral density (BMD) and hypertension in large cohorts of old male subjects. In this report, we further investigated whether this positive correlation between bone loss and hypertension could be also observed in animal models of hypertension. The use of animal models (Spontaneously Hypertensive Rats, SHR) can lead us to a better understanding of the correlation without other confounding factors. We used high-resolution micro-computed tomography to investigate the BMD and bone structure differences in the tibial and vertebral regions of two-year-old male SHRs in comparison to those in normotensive rats (Wistar-Kyoto, WKY). Moreover, we also applied the finite element analysis (FEA) and the bone biomarker test to further examine whether there are significant differences between these two groups. Surprisingly, almost all bone quality indices of the tibial region showed significant statistical differences (p<0.01) between the SHR and the WKY. In the tibial metaphysis part, the SHR group showed significant increase in the bone fraction (BV/TV, 29.5%), bone number (Tb.N, 31.4%), connectivity density of bones (Conn.D, 138%), and decrease in the bone separation (Tb.Sp, -27.9%), cortical thickness (Ct.Th, -18.2%), cortical bone density (Ct.TMD, -1.9%), and structure model index (SMI, -21.6). In addition, the 2-dimensional histomorphometric scan on the tibial diaphysis region also showed that the bone quality is better in SHR than WKY rats. On the contrary, SHRs significantly lost concentrations of two bone formation markers (Vitamin D25H and P1NP), and had elevated S-CTX concentrations (a bone resorption marker) compared to WKYs. In this reports we revealed that even the loss of bone mass continued happening in old-male SHRs, through the changes of bone microarchitectures, the bone quality was getting better at the same time.

The onset of Alzheimer’s Disease (AD) may begin up to 20 years before clinical symptoms are apparent. It is a challenge for clinicians to treat, as the best medical outcome is temporarily slowing the onset of the disease before it becomes ultimately fatal. Due to economic and social pressure AD places on the affected individual and their families, it is particularly burdensome to low-to-middle income countries (LMCIs). Thankfully, cutting-edge deep learning (DL) models are being developed to predict the diagnosis of AD before clinical symptoms manifest. These DL models most commonly use the biomarker fluorodeoxyglucose (FDG), although amyloid-PET (florbetapir) has also become prevalent. FDG is the more accessible and affordable biomarker, whereas, florbetapir detects the amyloid plaque that is theorized to be directly responsible for the neuronal death in AD and may be the better detector of the disease. To determine the most practical biomarker for LMICs, we utilized low-resolution datasets of FDG-PET and amyloid-PET provided by the Alzheimer’s Disease Neuroimaging Initiative to train two DL models with a 3D image classification framework. The FDG-PET and amyloid-PET models resulted in AUCs of 0.919 and 0.891 on their respective test sets. We conclude the difference of DL performance between the two biomarkers trained on low-resolution PET data is negligible. Thereby, as the modestly priced and universal biomarker, FDG-PET is the practical option for LMICs and other financially vulnerable communities for the prediction of a future AD diagnosis.

Purpose: Neuroblastoma is an embryonic tumor of the peripheral sympathetic nervous system. Most of neuroblastoma tumors express norepinephrine transporter (NET), which makes metaiodobenzylguanidine (mIBG), an analogue of norepinephrine, an ideal tumor specific agent for therapy, when labeled with I-131. Although drug therapies of neuroblastoma are performed regularly, there is lack of accurate quantitative assessment of tumor response to the therapy. This study was carried out with the objectives: the development of a novel 18F-labeled small molecule-imaging agent that targets the human NET (hNET) receptor, the establishment of a quantitative methodology to assess the therapeutic effect of [131I]mIBG and the establishment of murine xenograft model with a human neuroblastoma cell line that overexpresses hNET for better mIBG uptake would fill an unmet need to further develop treatment for this disease.

Methods: In order to enhance mIBG uptake for therapy, luciferase-expressing and hNET-transduced NB1691 (NB1691-luc-hNET) cells were implanted subcutaneously and in the renal capsule of murine xenograft models. Once the tumors reached a defined volume, the mice were injected with the [18F]RP-109, a NET imaging agent and scanned on the microPET/CT instrument. The xenografts were also imaged using bioluminescence to assess the viability of the cells in vivo. The mice were then treated with [131I]mIBG using an established protocol. Three weeks after the [131I]mIBG treatment, they were re-imaged on the microPET/CT using [18F]RP-109 as well as by bioluminescence. The PET images were then correlated with the bioluminescence scans as well as tumor volume measurements to assess the utility of the probe for monitoring therapy response of the tumors.

Results: The novel probe, [18F]RP-109, was successfully prepared and evaluated in neuroblastoma, but no tumor uptake was observed. The treatment of neuroblastoma with [131I]mIBG therapy showed a better response with higher dose of [131I]mIBG. The therapeutic data obtained from the bioluminescence imaging helps to assess the effectiveness of [131I]mIBG treatment of neuroblastoma model and evaluate the functional status of tumors.

Conclusion: The NET probe was successfully radiolabelled with fluorine-18 and it did not show any visible uptake in the tumors that overexpress hNET. The [131I]MIBG therapy study in mouse models using bioluminescence and tumor volume measurement as follow-up showed the effective therapy at 2 mCi level, which was consistent with the estimated tumor dosimetry study performed previously.

A technology for imaging extremely low photon flux is an unmet need, especially in targeted alpha therapy (TAT) imaging, which requires significantly improved sensitivity to detect as many photons as possible while retaining a reasonable spatial resolution. This dissertation focuses on addressing this need through the exploration of novel technologies for ultra-low activity collimatorless nuclear imaging. Additionally, the dissertation investigates the application of radionuclide dosimetry analysis, which plays a crucial role in therapeutic procedures.

Conventional gamma cameras, with their collimators, reject a significant number of photons, including primary and scattered photons, rendering them unsuitable for photon-starved imaging scenarios like TAT. To overcome this limitation, we propose collimatorless imaging for ultra-low activity imaging, which involves removing the collimator in conventional gamma cameras and positioning the detector as close as possible to the phantom. To enable reconstruction for collimatorless imaging, innovative image reconstruction algorithms are proposed to overcome the challenges posed by the lack of collimation. We develop the min-min weighted robust least squares (WRLS) algorithm and the Masked-MLEM (maximum likelihood expectation maximization) algorithm to provide robust reconstructions in the presence of uncertainties in the projection data and the system matrix.

In addition to advanced image reconstruction algorithms, the dissertation explores the design and optimization of collimatorless imaging systems for fast imaging and ultra-low activity imaging applications. Specifically, we develop the dual-layer collimatorless single photon emission computed tomography (SPECT) systems that optimize sensitivity, spatial resolution, and overall imaging performance. These systems enable simultaneous acquisition of collimatorless and collimated projections, combining the advantages of collimatorless imaging (high sensitivity) and collimated detection (improved spatial resolution).

Furthermore, the dissertation investigates the feasibility of using image values obtained from one radiotracer to estimate the absorbed doses of its theranostic pairs. This is exemplified by investigating the relationship between the uptake of 68Ga-DOTA-TATE and 177Lu-DOTA-TATE in organs and tumors in laboratory mice.

By addressing these key aspects, this dissertation contributes to the advancement of ultra-low activity collimatorless nuclear imaging and radionuclide dosimetry analysis, enabling improved imaging capabilities and enhanced dosimetry estimation for targeted radionuclide therapy.