SYNTHESIS, BIODISTRIBUTION AND RENAL HANDLING OF VARIOUS CHELATE-SOMATOSTATIN CONJUGATES WITH METABOLIZABLE LINKING GROUPS

A series of DTPA-octreotide conjugates, with various linking groups, w ere synthesised to investigate the effect of different metabolizable l inkers on the renal retention of radioactivity. All these newly synthe sised octreotide conjugates retained the high binding affinity of octr eotide for the somatostatin (SRIF) receptors either when unlabeled or radiolabeled with In-111. Some of the metabolizable linkers were rapid ly degraded in vitro when incubated with a kidney homogenate. However, in vivo, all these conjugates displayed a significantly lower uptake in SRIF receptor-positive tissue compared to two conjugates with short , stable linkers, Additionally, the compounds with a potentially metab olizable linker had a higher whore-body retention of activity as oppos ed to the three metabolically stable compounds. Several of the linkers gave evidence of cleavage while in circulation in the blood, and it i s probable that the lower tumour accumulation of most of the compounds tested was low due to the high enzymatic nature of the exocrine pancr eatic tumour model used. In short, no increase in the tumour-to-kidney ratio was achieved with the analogues containing a metabolizable link er. The highest target-to-nontarget tissue ratios were obtained for th e DTPA-octreotide conjugates that had short, metabolically stable link ers. (C) 1997 Elsevier Science Inc.