Date of Award
Doctor of Philosophy (PhD)
R. A. Bell
Because of its availability and favorable disintegration characteristics, there has been interest in recent years to bind technetium-99m (⁹⁹ᵐTc) to carrier molecules for use as tissue-specific diagnostic radiopharmaceuticals. In contribution to this effort, this thesis describes some investigations into the synthesis and NMR spectroscopy of novel bifunctional chelants for Tc radioimaging. Using bifunctional chelate strategies, a series of diamide disulfur (DADS) ligand conjugates of biologically active, carrier compounds were prepared for development into prospective myocardial and gastroenterological imaging agents. Carrier molecules of the intended myocardial agents included cardioactive compounds, such as C₁₁ and C₁₆ long chain fatty acids and the cardenolide aglycone digitoxigenin. DADS ligand derivatives of cholic acid, taurine and β-cyclodextrin were also synthesized in an effort to determine their potential utility as gastroenterological technetium imaging agents. The conjugation of ligands to steroidal molecules represents a new approach towards the production of ⁹⁹ᵐTc-based radiopharmaceuticals. The 10-membered heterocycle, N,N'-[dimethyl-(2,2'-dithiobisethanoyl)] ethylenediamine (40), was prepared to aid in the interpretation of the complex NMR spectral characteristics observed in many of the DADS ligands. It exists in solution as a mixture of two Z,Z and on Z,E disulfide and amide ring conformers and has been characterized by NOE, ¹H-¹H, ¹H-¹³C shift correlated NMR and molecular modelling studies. Among the Z,Z ring conformers, Z,Z₁ and Z,Z₂, the former predominates and interconverts with the latter isomer by rotation about the S-S bond with an apparent activation energy of 14.5 ± 1.3 kcal/mol. Coalescence of N-CH₃ signals occurred at about 127℃ at 500 MHz, which corresponded to an approximate barrier to amide rotation of 19.3 kcal/mol. Aromatic solvent induced shifts (ASIS) in C₆D₆ have corroborated molecular mechanics and NOE predictions of stereochemistry. The structure of the Z,E stereoisomer of 40 has been determined by single crystal X-ray diffraction at 296 K. A large geminal N-CH₂ inequivalence (>2 ppm in CDCl₃) was seen in the Z,Z conformers. Based on empirical calculations of chemical shifts, roughly one-half of the observed splitting was rationalized in terms of nearly equal contributions from magnetic anisotropy and electric field shielding mechanisms of the amide carbonyl groups. An implication of these results is the possibility of using α-CH (and eventually -CH) shifts to probe the local conformational space in structured proteins and other complex amides.
Maharajh, Rabindranath Bansee, "Synthesis and NMR spectroscopy of N,N'-bis(2-thioethanoyl)-2,3-diaminopropanoic acid derived carrier chelants for technetium radioimaging" (1993). Open Access Dissertations and Theses. Paper 3872.