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

Abstract

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 68 Ga (G-Ob) into the lumbar space of three baboons. We also studied unconjugated DTPA labeled with 68 Ga, 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.

Decreased blood–brain leptin transfer in an ovine model of obesity and weight loss: resolving the cause of leptin resistance

“…The benefits of administering leptin to improve the success of weight loss programmes for the obese have been recognized. 20 Research efforts have also recognized the need to enhance leptin entry into the brain to improve its therapeutic efficacy, 21 for example by intrathecal injection 22 or by modifying the molecule to produce a leptin with improved permeation across the blood-brain barrier, 23 and our study clearly endorses the rationale for this approach. An increased understanding of the causes of the impaired transport would clearly help in this regard.…”

Characteristics of compounds that cross the blood-brain barrier

“…For example, intrathecal administration for delivery of drug to the brain is ineffectual for small, lipid soluble drugs [ 33 ]. However, this route may be an option for large regulatory proteins with negligible brain-to-blood efflux [ 34 ]. Intranasal delivery of drugs, including peptides [ 35 ], shows a great deal of promise [ 36 ].…”

PET Imaging of Leptin Biodistribution and Metabolism in Rodents and Primates

“…PET is well suited for studies of the biodistribution of hormones due to its mm scale resolution, high sensitivity, and ease of quantification (Bailey et al, 2005). While a previous report used PET imaging to study the CNS distribution of leptin following intrathecal injection (McCarthy et al, 2002), PET imaging has not been used to comprehensively study leptin's systemic biodistribution. Here we describe the development of two positron labeled leptin tracers, 18 F-FBA-leptin and 68 Ga-DOTA-leptin.…”