Many therapeutic leads fail to advance clinically because of bioavailability, selectivity, and formulation problems. These problems can be solved either by modifying the drug itself, creating a prodrug or attaching a molecular transporter. Chapter 1 reviews common prodrug strategies with an emphasis on release strategies, as release is also necessary for many transporter drug conjugates to be effective. Chapter 2 reviews the role of protein kinase C (PKC) in neurological disease. PKC has been proposed as a possible therapeutic target to treat three of the most common and deadly neurological diseases: Alzheimer's disease, stroke and amyotrophic lateral sclerosis. This chapter suggests ways in which small molecules that target PKC can be used to treat these diseases. Chapter 3 and 4 describe the use of molecular transporter linker conjugates to provide efficient drug delivery. Molecular transporter conjugates of otherwise poorly soluble or poorly bioavailable drugs or probes exhibit excellent solubility in water and biological fluids and at the same time an enhanced ability to enter tissues and cells and with modification to do so selectively. For many conjugates, however, it is necessary to release the drug/probe cargo from the transporter after uptake to achieve activity. Chapter 3 and 4 describe an imaging method that provides quantification of transporter conjugate uptake and cargo release in real-time in animal models. This method uses transgenic (luciferase) reporter mice and whole-body imaging, allowing noninvasive quantification of transporter conjugate uptake and probe (luciferin) release in real-time. Chapter 3 details a reducing environment activated release system that is shown to quickly release the cargo in cells and animals. Chapter 4 reports the studies on an esterase activatable release system and it is shown that this system is effective in cells and provides a different (slower and more sustained) release profile than that observed for the reducing environment triggered conjugates. Chapter 5 describes the synthesis and evaluation of lipidated guanidinium rich transporters. In cellular studies these compounds appeared to have slightly better uptake than nonlipidated transporters at lower concentrations, but proved to be cytotoxic at higher concentrations. Chapter 6 describes the efforts to find and synthesize small molecule mimetics of nerve growth factor (NGF). NGF has been shown to promote neurite outgrowth, neuronal differentiation and survival both in vivo and in vitro. NGF has also been found to be of critical importance to memory, learning, and depression. Even more exciting is NGF's neuroprotective activity. The major drawback of NGF is poor bioavailability. NGF does not cross the blood-brain barrier and as such must be administered by drilling a hole in the patient's head. One can either modify NGF with the hopes of increasing passage across the blood-brain barrier or find a small molecule with similar activity. In 2000 the small molecule kirkinine was isolated from the roots of Synaptolepis kirkii at low isolation yields. Kirkinine demonstrated NGF like activity at nanomolar concentrations. Chapter 6 describes efforts to synthesize kirkinine and kirkinine analogs to gain expertise with these complex scaffolds in order to use a structural basis to gain understanding of biological activity. One of the goals of this project is to understand function and use this deep understanding to make simplified, clinically-superior compounds.