PRECLINICAL EVALUATION OF TC-99M-LABELED SOMATOSTATIN RECEPTOR-BINDING PEPTIDES

We report here the results of studies on the in vitro receptor binding affinity, in vivo tumor uptake and biodistribution of two Tc-99m-labe led peptides. Methods: Peptides P587 and P829 were synthesized by N-al pha-Fmoc peptide chemistry, purified by reversed-phase HPLC and charac terized by fast-atom bombardment mass spectrometry. The peptides were labeled with Tc-99m by ligand exchange from Tc-99m-glucoheptonate. In vitro somatostatin receptors (SSTR)-binding affinities of P587, P829 a nd their oxorhenium complexes, [DTPA]octreotide and In-[DTPA]octreotid e were determined in an inhibition assay using AR42J rat pancreatic tu mor cell membranes and I-125-[Try(3)]somatostatin-14 as the probe. In vivo single- and dual-tracer studies of Tc-99m peptides and In-111-[DT PA]octreotide were carried out using Lewis rats bearing CA20948 rat pa ncreatic tumor implants. Results: Technetium-99m-P587 and Tc-99m-P829 of high-specific activity (>60 Ci (2.2 TBq)/mmole) were prepared in >9 0% radiochemical yield. P587 and P829 had a Ki = 2.5 nM and 10 nM, res pectively. [ReO]P587 and [ReO]P829, representing the Tc-99m complexes, had Ki = 0.15 nM and 0.32 nM, respectively. In comparison, [DTPA]octr eotide and In-[DTPA]octreotide had Ki = 1.6 and 1.2 nM, respectively. In vivo tumor uptake of Tc-99m-P587 and Tc-99m-P829 was high (4.1 and 4.9%ID/g at 90 min postinjection compared to 2.9% for In-111-[DTPA]oct reotide). Tumor/blood and tumor/muscle ratios at 90 min postinjection were 6 and 33 for Tc-99m-P587, 21 and 68 for Tc-99m-P829, and 22 and 6 4 for In-111[DTPA]octreotide. Conclusion: The high SSTR-binding affini ty acid high, receptor-specific and saturable in vivo tumor uptake ind icate that Tc-99m-P587 and Tc-99m-P829 are promising radiotracers for the clinical detection of SSTR-expressing tumors and other tissues by Tc-99m gamma scintigraphy.