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Date of Award

Fall 2011

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Supervisor

John F. Valliant

Language

English

Abstract

A series of new methodologies to link a neurotransmitter receptor targeting vector (WAY) to carboranes and the preparation of the corresponding metallocarboranes (M = Re, 99mTc) as a new class of organometallic CNS imaging probes is described. WAY-carboranes (5, 6, 16) and the corresponding metallocarboranes (M = Re (12, 13, 22a, 22b), 99mTc (14a, 15, 23)) were synthesized in yields ranging from 10-95%. The first observed 3,1,2 versus 2,1,8 rhenacarborane isomerization process was discovered for 12 where isomerization and complexation occurred simultaneously. Re-carboranes 22a and 22b had similar carbon-carbon cage configuration where electronic effects was the driving force behind isomerization.

The lipophilicities of 99mTc-carboranes (14a, 15, 23) were within the ideal range to cross the BBB (log P = 2.4-2.6). In vitro binding data showed that 22b has high affinity for alpha-adrenergic receptors (Ki = 17-39 nM) resulting in the first organometallic complex to effectively bind to this class of receptors. SPECT images of 14a in rats showed no brain uptake, while quantitative biodistribution studies indicated modest, non-negligible brain uptake in the hypothalamus region.

The neutral [M(CO)2(NO)(C2B9H10R)] analogues (30, 34, 37) were prepared to address the limited brain uptake of the [M(CO)3(C2B9H10R)]- complexes. Reactivity differences between Re and 99mTc 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 29 were measured.

Low yields and multistep syntheses associated with the preparation of substituted carborane led to the development of a carborane-alkyne platform. Alkyne-carboranes (53-55) were developed and conjugated to WAY-azide (46) using “click” chemistry. The metallocarboranes (M = Re (69-71), 99mTc (72-74)) were generated in yields ranging from 45-71%.

McMaster University Library

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