Radioiodine and 211At-labeled guanidinomethyl halobenzoyl octreotate conjugates:: potential peptide radiotherapeutics for somatostatin receptor-positive cancers

Derivatives of the somatostatin analogues octreotide and octreotate labeled with radioiosotopes are used in the diagnosis and therapy of somatostatin receptor (SSTR)-positive tumors. A method has been devised to synthesize N-(4-guanidinomethyl-3-iodobenzoyl)-Phe(1)-octreotate (GMIBO). Receptor binding assay and scatchard analysis yielded a K-d of 4.83 +/- 0.19 nM for this peptide. Derivatives of this peptide labeled with radioiodine ([*I]GMIBO) and the alpha-particle-emitting radiohalogen At-211 {N-(3-[At-211]astato-4-guanidinomethylbenzoyl)-Phe(1)-octreotate: [At-211]AGMBO} were prepared in a single step from a tin precursor in radiochemical yields of 30-35%, and 13-20%. respectively. Paired-label internalization assays performed with the SSTR-positive D341 Med human medulloblastoma cell line demonstrated that {I-125}GMIBO and [At-211]AGMBO were specifically internalized 20-40% more than N-alpha-(1-deoxy-D-frucosyl)-[I-131]I-Tyr(3)-octreotate ([I-131]I-Glu-TOCA), the radioiodinated octreotide derivative previously shown to exhibit maximum internalization in this cell line. Uptake of ([I-131]GMIBO in D341 Med subcutaneous xenografts in a murine model (8.34 +/- 1.82 versus 8.10 +/- 2.23%, ID/g at 1 h) and SSTR-expressing, normal tissues was comparable to that of [I-125]I-Glu-TOCA and was shown to be specific. However. the uptake of [I-131]GMIBO also was substantially higher in liver (16.9 +/- 3.15 versus 1.39 +/- 0.45% ID/g at 1 h) and in kidneys (44.33 +/- 6.47 versus 3.44 +/- 0.68%, ID/g at 1 h) compared to that of [I-125]I-Glu-TOCA, These data suggest that these novel peptide conjugates retail, their specificity for SSTR both in vitro and in vivo; however. because of their higher accumulation in normal tissues they would be best applied ill settings amenable to loco-regional administration such as medulloblastoma neoplastic meningitis. (C) 2004 Elsevier Inc. All rights reserved.