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Background: The intrathecal (IT) dosing route introduces drugs directly into the CSF to bypass the blood-brain barrier and gain direct access to the CNS. We evaluated the use of convective forces acting on the cerebrospinal fluid as a means for increasing rostral delivery of IT dosed radioactive tracer molecules and antisense oligonucleotides (ASO) in the monkey CNS. We also measured the cerebral spinal fluid (CSF) volume in a group of cynomolgus monkeys., Methods: There are three studies presented, in each of which cynomolgus monkeys were injected into the IT space with radioactive tracer molecules and/or ASO by lumbar puncture in either a low or high volume. The first study used the radioactive tracer 64 Cu-DOTA and PET imaging to evaluate the effect of the convective forces. The second study combined the injection of the radioactive tracer 99m Tc-DTPA and ASO, then used SPECT imaging and ex vivo tissue analysis of the effects of convective forces to bridge between the tracer and the ASO distributions. The third experiment evaluated the effects of different injection volumes on the distribution of an ASO. In the course of performing these studies we also measured the CSF volume in the subject monkeys by Magnetic Resonance Imaging., Results: It was consistently found that larger bolus dose volumes produced greater rostral distribution along the neuraxis. Thoracic percussive treatment also increased rostral distribution of low volume injections. There was little added benefit on distribution by combining the thoracic percussive treatment with the high-volume injection. The CSF volume of the monkeys was found to be 11.9 ± 1.6 cm 3 ., Conclusions: These results indicate that increasing convective forces after IT injection increases distribution of molecules up the neuraxis. In particular, the use of high IT injection volumes will be useful to increase rostral CNS distribution of therapeutic ASOs for CNS diseases in the clinic.

An accurate non-invasive method to determine total body cerebrospinal fluid volume has a number of potential diagnostic and therapeutic applications. Herein we describe a technique for automated segmentation of total body MRI data to determine cranial and spinal CSF volume in 15 healthy adults. These in vivo estimates of CSF volume exceed the standard reported volume of 150mL in human adults and provide normative data for diagnosis of disease states such as hydrocephalus and therapy including pharmacologic dosimetry. No correlation was observed between patient height or weight and total body CSF volume., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The intrathecal (IT) dosing route offers a seemingly obvious solution for delivering drugs directly to the central nervous system. However, gaps in understanding drug molecule behavior within the anatomically and kinetically unique environment of the mammalian IT space have impeded the establishment of pharmacokinetic principles for optimizing regional drug exposure along the neuraxis. Here, we have utilized high-resolution single-photon emission tomography with X-ray computed tomography to study the behavior of multiple molecular imaging tracers following an IT bolus injection, with supporting histology, autoradiography, block-face tomography, and MRI. Using simultaneous dual-isotope imaging, we demonstrate that the regional CNS tissue exposure of molecules with varying chemical properties is affected by IT space anatomy, cerebrospinal fluid (CSF) dynamics, CSF clearance routes, and the location and volume of the injected bolus. These imaging approaches can be used across species to optimize the safety and efficacy of IT drug therapy for neurological disorders.

Multi-modality molecular imaging techniques have expanded the role of imaging biomarkers in the pharmaceutical industry and are beginning to streamline the drug discovery and development process. The World Molecular Imaging Society (WMIS) serves as a forum for discussing innovative and exploratory multi-modal, interdisciplinary molecular imaging research with a mission of bridging the gap between pathology and in vivo imaging. To formalize the role of the WMIS in pharmaceutical research efforts, members of the society have formed an interest group entitled Advancing Drug Discovery and Development using Molecular Imaging (ADDMI). The ADDMI interest group launched their efforts at the 2016 World Molecular Imaging Congress by hosting a session of invited lectures on translational positron emission tomography (PET) imaging in the central nervous system. This article provides a synopsis of those lectures and frames the role of translational imaging biomarker strategies in the drug discovery and development process. [ABSTRACT FROM AUTHOR]

An accurate non-invasive method to determine total body cerebrospinal fluid volume has a number of potential diagnostic and therapeutic applications. Herein we describe a technique for automated segmentation of total body MRI data to determine cranial and spinal CSF volume in 15 healthy adults. These in vivo estimates of CSF volume exceed the standard reported volume of 150 mL in human adults and provide normative data for diagnosis of disease states such as hydrocephalus and therapy including pharmacologic dosimetry. No correlation was observed between patient height or weight and total body CSF volume. [ABSTRACT FROM AUTHOR]