John Chen MD,PhD, Presenter: Nothing to Disclose

Gloria Chiang MD, Abstract Co-Author: Nothing to Disclose

Elena Aikawa, Abstract Co-Author: Nothing to Disclose

Ralph Weissleder MD, PhD, Abstract Co-Author: Stockholder, VisEn Medical, Inc Consultant, Siemens AG

To determine whether a novel small molecule activatable MR agent targeting myeloperoxidase (MPO), an enzyme secreted by inflammatory cells in active demyelinating plaques in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis, can be used to increase the sensitivity and accuracy of active demyelinating lesion detection.

The MPO-sensitive agent bis-5HT-DTPA(Gd) was synthesized by the CMIR Chemistry Core. Acute EAE was induced in ten 8-week old SJL mice using proteolipid protein. 1-2 days after onset of clinical symptoms, MR imaging of the brain was performed on a 7T Bruker Pharmascan MRI scanner before and after intravenous injection of either 0.3 mmol/kg of DTPA(Gd) as control or 0.3 mmol/kg of bis-5HT-DTPA(Gd). Following imaging, animals were sacrificed and brains processed for immunohistochemistry for MPO (rabbit polyclonal anti-MPO) and macrophages (Mac-3).

In the presence of MPO, bis-5HT-DTPA(Gd) can be oligomerized and bind to proteins, causing increased T1-weighted signal and prolonged retention of the agent at sites of increased MPO activity. Lesions that only have blood-brain barrier breakdown without active inflammation exhibited similarly short time of enhancement with both agents (~30 min). However, Bis-5HT-DTPA(Gd) revealed significantly more lesions after contrast administration compared to those detected by DTPA(Gd) (p<0.05). These additional lesions remained enhanced even at 90 minutes after injection with the MPO-sensitive agent, consistent with MPO activation and retention of the agent in areas with MPO activity. Immunohistochemistry showed that these additional lesions were positive for MPO and corresponded also to areas of macrophage accumulation. Control brains did not stain positive for MPO or macrophages.

Molecular imaging agents targeting MPO increase the sensitivity of active inflammatory, demyelinating plaque detection, and allow differentiation of active from inactive lesions that only have BBB breakdown.

Multiple sclerosis imaging with MPO-sensitive agents will increase the sensitivity and accuracy of active lesion detection to allow early diagnosis and treatment.

Chen, J, Chiang, G, Aikawa, E, Weissleder, R, Imaging Active Demyelinating Plaques by Targeting Myeloperoxidase.  Radiological Society of North America 2006 Scientific Assembly and Annual Meeting, November 26 - December 1, 2006 ,Chicago IL. http://archive.rsna.org/2006/4431015.html