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Preclinical Comparison of ¹¹¹In-Labeled DTPA- or DOTA-Bombesin Analogs for Receptor-Targeted Scintigraphy and Radionuclide Therapy

¹ Department of Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
² Mallinckrodt Medical, St. Louis, Missouri
³ Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands

ABSTRACT

The 14-amino-acid peptide bombesin (BN) has a high affinity for the gastrin-releasing peptide (GRP) receptor that is expressed by a variety of tumors. Recently, high densities of GRP receptors were identified by in vitro receptor autoradiography in human prostate and breast carcinomas using [¹²⁵I-Tyr⁴]BN as radioligand. Radiometal-labeled diethylenetriaminepentaacetic acid (DTPA)-BN derivatives are potentially useful radioligands for receptor-targeted scintigraphy and radiotherapy of GRP receptor-expressing tumors. Methods: [DTPA-Pro¹,Tyr⁴]BN (A), [DOTA-Pro¹,Tyr⁴]BN (B), [DTPA--Lys³,Tyr⁴]BN (C), and [DOTA--Lys³,Tyr⁴]BN (D) (where DOTA is dodecanetetraacetic acid) were synthesized and studied for competition with binding of [¹²⁵I-Tyr⁴]BN to the GRP receptor. The ¹¹¹In-labeled BN analogs were studied in vitro for binding and internalization by GRP receptor-expressing CA20948 and AR42J pancreatic tumor cells as well as in vivo for tissue distribution in rats. Specific tissue binding was tested by coinjection of 0.1 mg [Tyr⁴]BN. Results: All BN analogs competitively inhibited the binding of [¹²⁵I-Tyr⁴]BN to the GRP receptor with 50% inhibitory concentration values in the range of 2–9 nmol/L. All ¹¹¹In-labeled analogs showed high and specific time- and temperature-dependent binding and internalization by CA20948 and AR42J cells. In in vivo studies, high and specific binding was found in GRP receptor-positive tissues such as pancreas (0.90, 1.2, 0.54, and 0.79 percentage injected dose per gram for A–D, respectively). In a rat model, the AR42J tumor could clearly be visualized by scintigraphy using [¹¹¹In-DTPA-Pro¹,Tyr⁴]BN as the radioligand. Although [¹¹¹In-DOTA-Pro¹,Tyr⁴]BN showed the highest uptake of radioactivity in GRP receptor-positive tissues as well as higher target-to-blood ratios, [¹¹¹In-DTPA-Pro¹,Tyr⁴]BN was easier to handle and is more practical to use. Therefore, we decided to start phase I studies with this DTPA-conjugated radioligand. Conclusion: [¹¹¹In-DTPA-Pro¹,Tyr⁴]BN is a promising radioligand for scintigraphy of GRP receptor-expressing tumors. We are currently performing a phase I study on patients with invasive prostate carcinoma.

Key Words: bombesin analogs • gastrin-releasing peptide receptor • receptor scintigraphy • DTPA • DOTA

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