TISSUE DISTRIBUTION AND METABOLISM OF RADIOIODINATED DTPA(0), D-TYR(1) AND TYR(3) DERIVATIVES OF OCTREOTIDE IN RATS

Lesions containing somatostatin receptors (SSR) in rats and in man can be visualized in vivo using radiolabeled octreotide (OCT) analogs: SS R scintigraphy was initially performed with [I-123-Tyr(3)]OCT and late r with [In-111-DTRA(0)]OCT. With the latter the residence time of radi oactivity (In-111) in SSR-positive targets is prolonged most probably due to the DTPA group. Therefore, we hypothesized that its presence mi ght also affect the metabolism of radioiodinated DTPA-OCT analogs. [D- Tyr(1)]OCT, [DTPA(0), D-Tyr(1)]OCT, [Tyr(3)]OCT and [DTPA(0), Tyr(3)]O CT were synthesized, and all 4 showed high and specific binding to the SSR in vitro, with IC50 values in the nanomolar range. The rare of in ternalization of the 4 radioiodinated OCT analogs by mouse AtT20 pitui tary tumors cells was in accordance with the IC50 values. The metaboli sm and tissue distribution of the 4 radioiodinated analogs were invest igated in rats at 4, 24 and 48 hours pi, and the tissue vs blood ratio s were calculated. High uptake of all OCT analogs was found in the som atostatin receptor-positive tissues at 4 hours, but only remained high at 24 and 48 hours with [I-125-D-Tyr(1)]OCT. and [DTPA(0),I-125-D-Tyr (1)]OCT. Kindey uptake of [I-125-D-Tyr(1)]OCT and [DTPA(0),I-125-D-Tyr (1)]OCT was also high. Blood clearance and disappearance from muscle w as rapid for all 4 analogs. Urinary excretion of [I-125-D-Tyr(1)]OCT, [DTPA(0),I-125-D-Tyr(1)]OCT,[I-125-Tyr(3)]OCT and [DTPA(0,125)I-Tyr(3) ]OCT amounted to 63%, 67%, 31% and 80% of injected dose respectively [ DTPA(0),I-125-D-Tyr(1)]OCT showed highest tissue to blood ratio and re sidence time in SSR-positive tissues, such as adrenals (ratio: 31, 79, and 66 at 4, 24 and 48 hours respectively) and pancreas (ratio: 14, 4 8 and 44 at 4, 24 and 48 hours respectively). Conclusion: The position of the Tyr residues and the addition of the DTPA group greatly influe nce the biodistribution of radioiodinated [Tyr]OCT analogs.