Amylin is co-secreted with insulin from the pancreas of patients with non-insulin dependent diabetes mellitus, and its deposition may contribute to the central nervous system (CNS) manifestations of this disease. Amylin, but not its mRNA, is found in brain, suggesting that CNS amylin is derived from the circulation. This would require amylin to cross the blood-brain barrier (BBB). We used multiple-time regression analysis to determine the unidirectional influx constant (Ki) of blood-borne, radioactively labeled amylin (I-Amy) into the brain of mice. The Ki was 8.99(10(-4)) ml/g-min and was not inhibited with doses up to 100 micrograms/kg, but it was inhibited by aluminum (Al). About 0.11 to 0.13 percent of the injected dose of I-Amy entered each gram of brain. Radioactivity recovered from brain and analyzed by HPLC showed that the majority of radioactivity taken up by the brain represented intact I-Amy. Capillary depletion confirmed that blood-borne I-Amy completely crossed the BBB to enter the parenchymal/interstitial fluid space of the cerebral cortex. Taken together, these results show that blood-borne amylin has access to brain tissue and may be involved in some of the CNS manifestations of diabetes mellitus.