Vol. 301, Issue 3, 878-883, June 2002

Positron Emission Tomography Shows that Intrathecal Leptin Reaches the Hypothalamus in Baboons

T. J. McCarthy, W. A. Banks, C. L. Farrell, S. Adamu, C. P. Derdeyn, A. Z. Snyder, R. Laforest, D. C. Litzinger, D. Martin, C. P. LeBel and M. J. Welch

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri (T.J.M., C.P.D., A.Z.S., R.L., M.J.W.); Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center-St. Louis, and Saint Louis University School of Medicine, Division of Geriatrics, Department of Internal Medicine, St. Louis, Missouri (W.A.B.); Amgen, Inc., Thousand Oaks, California (C.L.F., S.A., D.M., C.P.L); and Eli Lilly and Company, Indianapolis, Indiana (D.C.L.)

Human obesity may be caused by a resistance to circulating leptin. Evidence from rodents and humans suggests that a major component of this resistance is an impairment in the ability of the blood-brain barrier (BBB) to transport leptin from the blood to the brain. One potential way to bypass the BBB is by administering leptin into the intrathecal (i.t.) space. To be effective, i.t. leptin would have to move caudally from the site of injection, enter the cranium, and reach the hypothalamic arcuate nucleus at the base of the pituitary fossa. However, many substances, especially small, lipid-soluble molecules, do not diffuse far from the site of i.t. injection but are resorbed back into blood. To determine whether i.t. leptin can move caudally, we injected leptin conjugated to diethylenetriaminepentaacetic acid (DTPA) and labeled with ⁶⁸Ga (G-Ob) into the lumbar space of three baboons. We also studied unconjugated DTPA labeled with ⁶⁸Ga, which did not move up the spinal cord but rapidly appeared in blood after i.t. injection. In contrast, G-Ob steadily moved toward the cranium and had reached the hypothalamus 91 and 139 min after i.t. injection in two baboons. We estimated the concentration of leptin in the hypothalamic region to be at least 8 ng/ml, which is about 40 times higher than cerebrospinal fluid levels in normal weight humans and about 4 times higher than the highest level ever recorded after the peripheral administration of leptin. In a third baboon, the leptin neither moved caudally nor appeared in the blood. We conclude that leptin administered i.t. can reach the hypothalamus in therapeutic concentrations, although there is considerable individual variation.