Pre-clinical evaluation of [¹¹¹In-DTPA-Pro¹, Tyr⁴]bombesin, a new radioligand for bombesin-receptor scintigraphy

Bombesin (BN) is a 14-amino-acid neuropeptide with a high affinity for the gastrin-releasing peptide receptor. This receptor has been found to be expressed in a variety of tumours, including lung, breast, prostate and pancreas. A newly synthesized BN analogue, [DTPA-Pro¹, Tyr⁴]BN, was shown to be a high-affinity BN-receptor (BNR) agonist, stimulating prolactin secretion from 7315b cells with an IC₅₀ of 8 nM. The ¹¹¹In-labelled analogue was found to bind with high affinity to rat BNR in vitro and in vivo. The radioligand is internalized by BNR-expressing cells, in contrast to DTPA-conjugated BN antagonists. Therefore, we further studied the biodistribution of i.v. injected [¹¹¹In-DTPA-Pro¹, Tyr⁴]BN in rats. High and specific uptake was found in tissues of the gastrointestinal tract, notably pancreas. Uptake of radioactivity was blocked by pre- or co-injection of 100 μg [Tyr⁴]BN, but not when this was administered 30 min after the radioligand. This suggests BNR-mediated internalization of the radioligand within 30 min. The percentage injected dose (ID) taken up by BNR-positive tissues was a bell-shaped function of the amount (0.01-0.1 μg) of injected ligand. Next to the pancreas, highest uptake was observed in the kidneys, which was not blocked by excess [Tyr³]BN. Dynamic gamma camera studies showed rapid clearance of radioactivity from the blood compartment. Urinary excretion amounted to about 35% ID after 1 hr and to 70% ID after 24 hr, with a total body retention of 10% ID. Specific uptake was found in the BNR- positive CA20948 pancreas tumour and CC531 colon carcinoma in tumour-bearing rats. The CA20948 tumour, inoculated in the hindleg, was also visualized scintigraphically. [¹¹¹In-DTPA-Pro¹, Tyr⁴]BN appears to be a promising radioligand for scintigraphy of BNR-expressing tumours.