<p>A series of new methodologies to link a neurotransmitter receptor targeting vector (WAY) to carboranes and the preparation of the corresponding metallocarboranes (M = Re, <sup>99m</sup>Tc) as a new class of organometallic CNS imaging probes is described. WAY-carboranes (<strong>5</strong>, <strong>6</strong>, <strong>16</strong>) and the corresponding metallocarboranes (M = Re (<strong>12</strong>, <strong>13</strong>, <strong>22a</strong>, <strong>22b</strong>), <sup>99m</sup>Tc (<strong>14a</strong>, <strong>15</strong>, <strong>23</strong>)) were synthesized in yields ranging from 10-95%. The first observed 3,1,2 versus 2,1,8 rhenacarborane isomerization process was discovered for <strong>12</strong> where isomerization and complexation occurred simultaneously. Re-carboranes <strong>22a</strong> and <strong>22b</strong> had similar carbon-carbon cage configuration where electronic effects was the driving force behind isomerization.</p> <p>The lipophilicities of <sup>99m</sup>Tc-carboranes (<strong>14a</strong>, <strong>15</strong>, <strong>23)</strong> were within the ideal range to cross the BBB (log P = 2.4-2.6). <em>In vitro</em> binding data showed that <strong>22b</strong> has high affinity for alpha-adrenergic receptors (K<sub>i</sub> = 17-39 nM) resulting in the first organometallic complex to effectively bind to this class of receptors. SPECT images of <strong>14a</strong> in rats showed no brain uptake, while quantitative biodistribution studies indicated modest, non-negligible brain uptake in the hypothalamus region.</p> <p>The neutral [M(CO)<sub>2</sub>(NO)(C<sub>2</sub>B<sub>9</sub>H<sub>10</sub>R)] analogues (<strong>30</strong>, <strong>34</strong>, <strong>37</strong>) were prepared to address the limited brain uptake of the [M(CO)<sub>3</sub>(C<sub>2</sub>B<sub>9</sub>H<sub>10</sub>R)]<sup>-</sup> complexes. Reactivity differences between Re and <sup>99m</sup>Tc were noted during nitrosation conditions where the initial products from the reaction led to nitration of the phenyl group in addition to nitrosation of the metal core. The fluorescence properties of <strong>29</strong> were measured.</p> <p>Low yields and multistep syntheses associated with the preparation of substituted carborane led to the development of a carborane-alkyne platform. Alkyne-carboranes (<strong>53</strong>-<strong>55</strong>) were developed and conjugated to WAY-azide (<strong>46</strong>) using “click” chemistry. The metallocarboranes (M = Re (<strong>69</strong>-<strong>71</strong>), <sup>99m</sup>Tc (<strong>72</strong>-<strong>74</strong>)) were generated in yields ranging from 45-71%.</p> / Doctor of Philosophy (PhD)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/11241 |
| Date | 10 1900 |
| Creators | Louie, Anika S. |
| Contributors | Valliant, John F., Chemistry |
| Source Sets | McMaster University |
| Detected Language | English |
| Type | thesis |
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