RT Journal Article
SR Electronic
T1 Preclinical Comparison of <sup>111</sup>In-Labeled DTPA- or DOTA-Bombesin Analogs for Receptor-Targeted Scintigraphy and Radionuclide Therapy
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1650
OP 1656
VO 43
IS 12
A1 Breeman, Wouter A.P.
A1 de Jong, Marion
A1 Erion, Jack L.
A1 Bugaj, Joseph E.
A1 Srinivasan, Ananth
A1 Bernard, Bert F.
A1 Kwekkeboom, Dik J.
A1 Visser, Theo J.
A1 Krenning, Eric P.
YR 2002
UL http://jnm.snmjournals.org/content/43/12/1650.abstract
AB 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-ε-Lys3,Tyr4]BN (C), and [DOTA-ε-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.