Date of Award
Master of Science
The peptide hormone ghrelin contains a unique serine residue with a lipophilie n- octanoyl modification. In an effort to create an imaging probe targeting the growth hormone secretagogue receptor (GHSR), the design and synthesis of fluorine and rhenium containing ghrelin analogues through modification of this lipophilie chain are reported. Fluorine analogues were designed whereby the fluorine atom is situated at the terminus of an aliphatic chain. These side-chains were prepared from cyclic lactones and subsequently coupled to an on-resin truncated ghrelin(l-5) or ghrelin(l-14) with a diaminopropionic acid (Dpr) as residue-3. Fluorination then proceeded to yield the desired fluorine-bearing ghrelin analogues, the best of which had a 28 nM IC50 for GHSR. Ghrelin(l-14) analogues were also prepared containing rhenium, as a surrogate metal for the gamma emitter technetium-99m. In this instance, cyclopentadienyl rhenium tricarbonyl was added on-resin to the Dpr-3 modified ghrelin with the organometallic complex being situated at the terminus of the residue-3 side-chain, yielding compounds the best of which had a 35 nM ICso for GHSR. This lipophilic metal complex was situated within a region of the peptide ligand where a lipophilic mass is absolutely necessary for receptor binding. As such this represents a rare case of incorporating a metal into a peptide structure by an integrated design as opposed to the traditional conjugate approach. These derivatives demonstrate the ability to modify the Ser-3 side chain of ghrelin in order to create imaging probes for the GHSR, with fluorine-18 being used for PET imaging and technetium-99m for SPECT imaging.
Hyaluronan is a polysaccharide that is known to bind to the receptor for hyaluronic acid mediated motility (RHAMM). It has been found that hyaluronan has several
significant limitations as an imaging probe, therefore a hyaluronan mimetic peptide was chosen as it can serve a similar function while avoiding some of the shortcomings of hyaluronan such as enzymatic degradation by hyaluronidase. A fluorescence labeled imaging probe was designed and synthesized based on the hyaluronan mimetic peptide YDSeYeSe using a rhodamine-based dye. An in vitro cell evaluation wa conducted to asses the potency of this fluorescence imaging agent, showing that the agent could successfully bind to the cell surface receptor and be internalized. This experiment demonstrated the potential for developing a novel class of imaging probes based on the hyaluronan mimetic peptide.
Rosita, Dina, "Ghrelin Analogues as Potential Cancer Imaging Probes" (2008). Digitized Theses. 4370.