Alpha-melanotropin (alpha-melanocyte stimulating hormone, α-MSH) exerts its biological action by binding to specific receptors on the outer cell membranes of its target tissues with a high degree of affinity and specificity. Current evidence suggests that this takes place both in vitro and in vivo in both normal and malignant melanocytes. Thus, if it were possible to attach a radioisotope (e.g., ¹²⁵I) to α-MSH, or a suitable analogue, without interfering with the receptor affinity of the hormone, then a radioreceptor assay could be developed which would allow hormone-receptor interaction to be studied in detail. In addition, this radio-labeled melanotropin might be expected to accumulate in melanoma tumors in vivo thus facilitating tumor localization by nuclear imaging methods as has been successfully accomplished for thyroid tumors. The present studies were initiated to develop a radioactive melanotropin with full, or nearly full, biological activity. This labeled melanotropin must be of sufficient specific radioactivity to be suitable as a tracer in a radioreceptor assay and ultimately as a marker for in vivo tumor localization. The studies described herein provide information concerning: chloramine T induced iodination, lactoperoxidase catelyzed iodination, and iodogen induced iodination of α-MSH and certain structural analogues. Radio-labeled derivatives of various melanotropins were prepared using a variety of iodination techniques. Under conditions commonly used for the iodination of other peptides a substantial loss of biological activity of the native hormone (α-MSH) was observed. This loss of hormonal activity was primarily a consequence of oxidation of methinonine and occurred regardless of the oxidant used (chloramine T, lactoperoxidase-hydrogen perioxide, or iodogen). Under similar iodination conditions using 4-norleucine-alpha-melanotropin ([Nle⁴]-α-MSH), satisfactory incorporation of label into the peptide was accomplished without significant loss of biological activity. Data are presented suggesting that this peptide is far superior to α-MSH for use in the preparation of a radioactive melanotropin. Although some success was achieved using [Nle⁴]-α-MSH with all three iodination methods, the simplest and most consistent method involved the use of iodogen followed by purification of the labeled product using high performance liquid chromatography (HPLC). This importance of these studies in the development of a tracer for a radio-receptor assay and for in vivo localization of melanoma tumors is discussed.

Thesis (Ph.D.)--McMaster University, 2005. / Supervisor: John F. Valliant. Includes bibliographical references. Also available online.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Washington, 1997. / Includes bibliographical references (leaves [88]-96).

Thesis--Yale. / Includes bibliographical references (leaves 137-151).

Thesis--Reykjavík, 1976. / Summary in Icelandic. Includes bibliographical references (p. 180-185).

In recent years tumour hypoxia has been extensively investigated, mainly because it is a source of resistance to the common radio and chemo therapies. In fact, the low levels and heterogeneous distribution of oxygen in hypoxic microenvironment render ionizing radiation ineffective in treating cell proliferation. Furthermore, a low oxygen concentration promotes the activation of HIF-1 transcription factor, which favours the development of a more malignant and resistant cancer cell phenotype often associated with poor prognosis. Positron Emission Tomography (PET) imaging is a valuable diagnostic tool for investigating hypoxia in vivo by means of radiotracers, which incorporates both a radioisotope and a hypoxia-sensitive function. The aim of this multidisciplinary project was to develop small libraries of radiolabelled compounds starting from the biological and chemical features of the two gold standard hypoxia PET tracers [18F]FMISO and [18F]FAZA as well as those of the promising new tracer [18F]HX4. These new radiocompounds display the following peculiar structural characteristics: a 2-nitroimidazole hypoxia-sensitive moiety, different spacers to modulate steric constraint, lipophilicity and metabolic stability and a fluorinated aldopentose sugar as prosthetic group (e.g. [18F]FDR). Two series of compounds were designed and developed based on the conjugation method used to introduce the prosthetic group, namely the oxime bond formation and the thiazolidine ring closure. Six radiotracers belonging to the oxime-derivatives series were tested in vitro on MCF7 breast cancer cell lines in hypoxic conditions and a lead radiocompound incorporating a cyclopropyl group was identified. This new hypoxia tracer showed a better kinetic profile than both [18F]FMISO and [18F]FAZA in MCF7 cancer cell lines and comparable uptake values on a panel of different cancer cell lines, up to 120 min post administration at 1% of O2. These promising results will pave the way for futures in vivo studies.

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Call number: LD2668 .T4 1979 M34 / Master of Science