Analogs of somatostatin are being investigated clinically for the treatment of various malignancies, including brain tumors. We studied the ability of three therapeutically promising radioactively labeled somatostatin octapeptide analogs, RC-160, RC-121, and RC-161, to cross the blood-brain barrier (BBB) after peripheral or central injection. After i.v. injection, intact RC-160 was recovered from the blood and the brain. The entry rates were different for each compound but were generally low. By contrast, entry across the intact BBB increased 220 times when RC-160 was given in a serum-free perfusate. This suggests that some serum-related factor, probably the previously described protein binding or an aggregation-promoting factor, is the main determinant in limiting the blood-to-brain passage of somatostatin analogs. Entry into the brain was not inhibited by the addition of unlabeled analog to the perfusate, showing that passage was probably by diffusion across the membranes that comprise the BBB rather than by saturable transport. By contrast, a saturable system was found to transport peptide out of the central nervous system (CNS). The clearance from the CNS of RC-160 and RC-121, but not RC-161, was faster than could be accounted for by reabsorption of cerebrospinal fluid. Transport of radioactively labeled RC-160 out of the CNS was inhibited by unlabeled RC-160 or somatostatin but was not affected by some other peptides known to cross the BBB by their own transport systems. More than 80% of the radioactivity recovered from the blood after intracerebroventricular injection of RC-160 was eluted by HPLC at the position of the labeled analog, showing that the peptide had crossed the BBB in intact form. Our results indicate the presence of a saturable transport system in one direction across the BBB for some superactive analogs of somatostatin. Several problems impede the therapeutic use of naturally occurring peptides, including poor absorption by the gastrointestinal tract, a short half-life in the circulation, and multiple actions. For use in the central nervous system (CNS), limited passage across the blood-brain barrier (BBB) may also be a factor. Most of these problems have been solved in the case of somatostatin by the development of analogs. Circulating half-life has been increased by the development of enzymatically resistant analogs. In addition, the administration of the analogs in sustained-delivery systems (microcapsules) permits the maintenance of high therapeutic blood levels (6, 10, 17). Many analogs show selectivity in their activities. For example, RC-121 is about 100 times more potent than somatostatin-(1-14) tetradecapeptide in the inhibition of growth hormone release but <5 times more potent in the inhibition of gastric acid release (17,18).In contrast, essentially no work has been done to investigate the ability of somatostatin analogs to cross the BBB, although it is known that radioactively iodinated Tyrsomatostatin-(1-14) pentadecapeptide can cross (19). This relationship to the BBB...
