title: Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery.
abstract: 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.
authors.affiliation: Experimental Medicine, Biogen Inc., Cambridge, Massachusetts, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Wolf
authors.affiliation: inviCRO LLC, Boston, Massachusetts, USA.
authors.forename: Jacob Y
authors.initials: JY
authors.lastname: Hesterman
authors.affiliation: inviCRO LLC, Boston, Massachusetts, USA.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Sullivan
authors.affiliation: inviCRO LLC, Boston, Massachusetts, USA.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Orcutt
authors.affiliation: inviCRO LLC, Boston, Massachusetts, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Silva
authors.affiliation: inviCRO LLC, Boston, Massachusetts, USA.
authors.forename: Merryl
authors.initials: M
authors.lastname: Lobo
authors.affiliation: inviCRO LLC, Boston, Massachusetts, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Wellman
authors.affiliation: inviCRO LLC, Boston, Massachusetts, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Hoppin
authors.affiliation: Experimental Medicine, Biogen Inc., Cambridge, Massachusetts, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Verma
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000000981:diagnostic imaging*; D002555:Cerebrospinal Fluid; D016503:Drug Delivery Systems; D006801:Humans; D007278:Injections, Spinal; D007554:Isotopes; D008279:Magnetic Resonance Imaging; D057054:Molecular Imaging; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D000075462:Serum Albumin, Human; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D007554:Isotopes; D000075462:Serum Albumin, Human