Medicinal-Pharmaceutical Chemistry Commons^™

The Development Of Fluorine-18 Imaging Agents Targeting The Ghsr, Marina D. Childs

Electronic Thesis and Dissertation Repository

Molecular imaging is an interdisciplinary field of study that allows for real-time visualization of biological processes in both healthy and disease states. Fluorine-18 positron emission tomography (PET) imaging is a highly sensitive technique where molecular probes containing fluorine-18 serve to specifically locate and visualize the expression of relevant disease biomarkers. The growth hormone secretagogue receptor 1a (GHSR) is differentially expressed in cancer and cardiac pathology, making it a biomarker of interest for imaging such diseases. This thesis discusses the development and optimization of GHSR-targeting ¹⁸F-PET imaging probes as well as proposes a new imaging agent discovery technique.

Chapter 2 …

Synthesis And Characterization Of Peptide Nucleic Acids Incorporating Modified Nucleobases, Ali Heidari

Electronic Thesis and Dissertation Repository

Peptide Nucleic Acid (PNA), is a mimic of natural nucleic acids with exceptional binding properties. As such, numerous applications in biochemistry, medicine and biotechnology for PNA exist or have been proposed so far. Pseudo-complementary PNAs containing diaminopurine and thiouracil base pairs have been prepared and are shown to bind with high specificity and efficiency to complementary targets in double-stranded DNA by a mechanism termed ‘‘double duplex invasion’’ in which the duplex is unwound and both DNA strands are targeted simultaneously, each by one of the two pseudo-complementary PNAs. Chapter 2 describes a method for the preparation of modified nucleic acids …

Incorporation Of Fluorine Into Peptides And One-Bead One-Compound Libraries Through Copper-Free Click Chemistry For The Discovery Of Radiopharmaceuticals, Emily M. Murrell

Electronic Thesis and Dissertation Repository

Molecular imaging is making possible the understanding of intricate biological processes in real-time in both healthy and diseased tissues. The ability to non-invasively locate biomarkers of disease with good sensitivity and specificity affords the ability to provide accurate and early diagnoses, and patient stratification for therapy. The chemokine receptor CXCR4 is one biomarker of interest, as it is overexpressed in many cancers, yet has low expression elsewhere in normal physiology. This thesis will document a method of combinatorial chemistry to construct libraries of new potential peptide-based imaging agents for positron emission tomography (PET) imaging. It will also incorporate the study …

Non-Traditional Metallation Of Metallothioneins With Xenobiotic Therapeutic Metals, Daisy L. Wong

Electronic Thesis and Dissertation Repository

The rise of the Anthropocene has seen more global pollution than before in history. With the explosion of consumer electronics in the last half century, the rise of metal pollution from their extraction and disposal results in the unnatural introduction of heavy and rare metals into the ecosystem. Organisms have a metal defense protein, metallothionein, which has multiple roles in essential metal regulation and protection against minimal toxic metal exposure. However, these modern heavy metals prominent in electronics are not found biologically and their interactions in the body are generally unknown. Some of these metals are employed as therapeutic agents …

Design, Synthesis, And Evaluation Of Novel Protease-Activated Receptor 2 (Par2)-Targeting Imaging Agents For Cancer, Jordan C. Lesarge

Electronic Thesis and Dissertation Repository

Aberrant function and over-expression of protease-activated receptor 2 (PAR2), a GPCR, is associated with various cancers and inflammatory diseases. PAR2-targeting ligands have been developed with therapeutic applications but the development of imaging probes is lacking. A series of PAR2-targeted fluorescent and ¹⁸F-PET imaging agents were synthesized and assessed for PAR2-binding. A novel dye-conjugated peptide, Isox-Cha-Chg-ARK(Sulfo-Cy5)-NH₂ (EC₅₀=16nM, K_D=38nM), showed >10-fold increase in potency and binding affinity for PAR2 compared to the leading known fluorescent probe. A novel PET imaging ¹⁸F-labeled peptide, Isox-Cha-Chg-AR-Dpr([¹⁸F]4-FB)-NH₂, is the first PAR2-targeted in vivo imaging agent. …

The Development Of Platforms For Inhibiting Rhamm-Ha Interactions & The Development Of An Optical Probe For Measuring Glomerular Filtration Rate, Alexandra Hauser-Kawaguchi

Electronic Thesis and Dissertation Repository

Carbohydrates are a class of molecule occurring widely in the body. Their presence has varied biological implications, generating clinical interest regarding their impact on disease prognosis. This thesis will investigate the development of chemical entities surrounding two carbohydrates, hyaluronan and inulin.

The Receptor for hyaluronan mediated motility (RHAMM) is one of several receptors for hyaluronan (HA), a polysaccharide that, when fragmented, has pro-angiogenic and inflammatory properties. RHAMM expression is tightly regulated during homeostasis but increases in response to cellular stress, including during injury or disease states. HA-RHAMM interactions stimulate the Ras-ERK-Mek pathway to promote cell motility, differentiation, and proliferation. Specific …

Poly(Ethyl Glyoxylate) Solid-Core Particles For Drug Delivery, Michael Thomas Gambles

Electronic Thesis and Dissertation Repository

The ability to trigger the degradation of polymeric nanoparticles (NPs) by a specific stimulus can provide a method of improved drug targeting and selective release capabilities in vivo. The challenge for most polymeric drug delivery systems remains the necessity for many stimuli events to trigger the release of cargo. Polymeric nanotechnology containing “self-immolative polymers” looks to alleviate the reliance on high concentrations of stimuli by undergoing complete end-to-end depolymerization via a single stimulus-mediated reaction of an end-cap. Herein, NPs were developed using poly(ethyl glyoxylate) (PEtG) blended with poly(d,l-lactic acid) (PLA) to encapsulate a hydrophobic cargo to be released upon …

Crystal Engineering Of Active Pharmaceutical Ingredients With Low Aqueous Solubility And Bioavailability, Jenna M. Skieneh

Electronic Thesis and Dissertation Repository

Approximately 75% of new molecular entities approved by the Food and Drug Administration (FDA) for use in the pharmaceutical industry are found to have poor aqueous solubility. This undesirable attribute leads to consequences such as higher doses required to reach therapeutic levels, greater vulnerability to food effects, lesser fraction absorbed in the small intestine and damage to the environment due to increased quantity of excretion. The addition of an excipient (i.e. a FDA approved inactive ingredient) to the molecular structure of an active pharmaceutical ingredient (API) through intermolecular bonding is of growing interest because the properties of the API can …

The Design And Synthesis Of Ghrelin Analogues As Non‐Invasive Ghs‐R1a Imaging Probes, Carlie L. Charlton

Electronic Thesis and Dissertation Repository

The field of molecular imaging is constantly growing and evolving in order to provide the best possible healthcare for patients in various stages of disease and therapy. Molecular imaging aims to locate specific markers of disease by selectively targeting the markers of interest with high selectivity and visualizing the accumulation using external detection. The growth hormone secretagogue receptor-1a (GHS-R1a) has been shown to be involved in various important biological functions such as energy homeostasis and cardiac contractility. GHS-R1a has shown involvement in proliferation, migration and cell invasion of specific cancer subtypes. Therefore, targeting GHS-R1a is an important marker of different …

Design, Synthesis, And Reactivity Of Bimetallic Complexes Of Dimethylplatinum(Ii) Containing Ditopic Ligands, Matthew S. Mccready

Electronic Thesis and Dissertation Repository

This thesis describes a study of monometallic and bimetallic dimethylplatinum(II) complexes containing ditopic nitrogen donor ligands. This work details the design and synthesis of side-to-side and cofacial arranged ligands and their respective coordination chemistry. The study of the synthesis, characterization and reaction mechanisms of the various dimethylplatinum(II) complexes is outlined in detail with special emphasis focused on the reactivity of the complexes towards oxidative addition.

The ditopic ligand 6-dppd, 1,4-di(2-pyridyl)-5,6,7,8,9,10-hexahydrocycloocta[d]pyridazine, was observed to coordinate only a single equivalent of a platinum(II) center. The inability to coordinate a second equivalent, even through an assisted bridging atom, is presumed to be due …

Development Of A Gallium-Containing One-Bead One-Compound Peptide Library For The Discovery Of New Molecular Imaging Probes, Fernanda C. Bononi

Electronic Thesis and Dissertation Repository

An eight amino acid one-bead one-compound (OBOC) peptide library, containing a gallium-DOTA complex, was developed in an attempt to overcome common issues associated with the later addition of radionuclides to peptide chains of imaging probes. The further addition of a radionuclide often changes the binding properties of a peptide, as it adds bulk, and possibly charges. MALDI (matrix-assisted laser desorption ionization) tandem mass spectrometry was determined to be the method of choice in order to deconvolute gallium-containing peptide sequences. The library obtained was screened against the breast cancer cell lines MDA-MB-231 and MCF-7. Positive beads were isolated and sequences were …

Peptidomimetic Ghs-R1a Agonists As Pet Imaging Agents For Prostate Cancer, Milan M. Fowkes

Electronic Thesis and Dissertation Repository

Contemporary diagnostic techniques for prostate cancer (PCa) have a limited ability to distinguish between benign and malignant disease. The ghrelin receptor has a differential expression in normal, benign and cancerous prostatic tissue. Targeting this receptor with 18F-radiolabelled peptidomimetics would enable differentiation between these disease states via PET imaging. A series of 19F-peptidomimetics were synthesized and characterized by HRMS, HPLC and 1 H-NMR spectroscopy in order to test locations for 18F radioisotope insertion. Competitive receptor binding assays using HEK293/GHS-R1a cells were used to evaluate compound binding affinities. This led to the identification of two lead compounds: [1-Nal4,Lys5(4-FB)]G-7039 (IC50 = 69 nM) …

Carboxylic Acid Functionalized Butyl Rubber: From Synthesis To Applications, Matthew John Mceachran

Electronic Thesis and Dissertation Repository

Butyl Rubber (RB) is a copolymer of isobutylene (IB) with small percentages of isoprene (IP). Typically these IP units serve as sites for the covalent cross-linking of the rubber, but they can also serve as sites to further functionalize RB. These modifications can expand the potential applications of RB. This thesis describes the synthesis of carboxylic acid functionalized RB and some properties and applications of these materials.

The Development Of Organometallic Oboc Peptide Libraries For Use In Molecular Imaging, Dana R. Cruickshank

Electronic Thesis and Dissertation Repository

The discovery of peptide-based targeted imaging agents is hindered by the required addition of a radionuclide that can affect the binding properties of the peptide. Screening of peptide libraries is problematic because they do not take into account the presence of the imaging agent. Herein the development of an organometallic OBOC peptide library that contain a rhenium (I) tricarbonyl-based imaging entity surrogate incorporated directly onto the peptide chain, is reported. Additionally, MALDI tandem mass spectrometry is reported as a method to deconvolute organometallic peptides containing four different rhenium (I) tricarbonyl chelates on the N-terminus of octapeptides. Furthermore, an organometallic OBOC …

Development Of Single And Multimodality Imaging Probes For Pet, Spect And Fluorescence Imaging, Babak Behnam Azad

Electronic Thesis and Dissertation Repository

This dissertation is in an integrated format discussing three major projects centered around probe development. In the first project, novel metal-chelated and fluorinated GLP-1 derivatives were prepared all containing D-Ala-8, a modification known to improve resistance towards degradation by dipeptidyl-peptidase IV. The effect of increased distance between DOTA and the peptide chain was investigated using a spacer, in order to reduce steric effects imposed by DOTA. Placement of linker and DOTA moieties were varied within the GLP-1 sequence to test for optimal metal-complex location. Binding affinity of peptide derivatives was determined in vitro with CHO/GLP-1R cell line and shown to …