SPECT imaging of direct nose-to-brain transfer of a peptide in man

November 12, 2013

Purpose: In multiple species, intranasal administration of drug has been shown to bypass the blood-brain-barrier and deliver drugs directly to the central nervous system (CNS). This route of delivery has the potential to enable many therapeutics, including peptide and proteins, to reach the CNS in effective concentrations and could have a significant impact in the treatment of CNS diseases. In this study, SPECT imaging was used to visualize this direct nose-to-brain transfer in man for the first time.

Methods: Seven subjects were enrolled in this study. MAG-3, a technetium-99 labeled peptide, was delivered as the radiotracer. This study used a two arm cross over design to investigate MAG-3 administration with the Impel Precision Olfactory Delivery (POD) nasal device in comparison with a traditional nasal pump. Imaging was performed on two separate days, one week apart. After tracer administration, 2D SPECT imaging was performed for 5 minutes. Then, 3D SPECT was acquired for 10 minutes starting at 10 minutes after tracer administration.

Results: The POD nasal device resulted in a large fraction of dose being deposited in the upper third of the nasal cavity after administration. The traditional nasal pump resulted in a majority of the dose being deposited in the vestibule portion of the nasal cavity. With the traditional nasal pump there was no observable transfer of the peptide tracer from the nasal cavity to the central nervous system. In contrast, after POD administration the tracer could be observed in the basal membranes of the brain and other brain regions in a distribution pattern similar to what has been observed in several preclinical studies on nose-to-brain transport.  No significant amount of tracer was observed in muscle tissue, indicating a direct nose-to-brain transfer.

Conclusions: The Impel POD device was superior in depositing the peptide tracer into the upper third of the nasal cavity where connections exist between the nasal cavity and the CNS. This nasal distribution appears critical to enable direct transfer of compound from the nasal cavity to the central nervous system along the nose-to-brain distribution pathways. This study has confirmed the nose-to-brain transport pathways in humans for the first time using SPECT imaging and validates the utility of this pathway to deliver biologic therapeutics to the CNS.