title: Pre-clinical evaluation of [(111)In-DTPA-Pro(1), Tyr(4)]bombesin, a new radioligand for bombesin-receptor scintigraphy.
abstract: 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-Pro(1),Tyr(4)]BN, was shown to be a high-affinity BN-receptor (BNR) agonist, stimulating prolactin secretion from 7315b cells with an IC(50) of 8 nM. The (111)In-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 [(111)In-DTPA-Pro(1),Tyr(4)]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 microgram [Tyr(4)]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 microgram) of injected ligand. Next to the pancreas, highest uptake was observed in the kidneys, which was not blocked by excess [Tyr(4)]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. [(111)In-DTPA-Pro(1), Tyr(4)]BN appears to be a promising radioligand for scintigraphy of BNR-expressing tumours.
authors.affiliation: Department of Nuclear Medicine, University Hospital "Dijkzigt," Rotterdam, The Netherlands. breeman@nuge.azr.nl
authors.forename: W A
authors.initials: WA
authors.lastname: Breeman
authors.forename: M
authors.initials: M
authors.lastname: De Jong
authors.forename: B F
authors.initials: BF
authors.lastname: Bernard
authors.forename: D J
authors.initials: DJ
authors.lastname: Kwekkeboom
authors.forename: A
authors.initials: A
authors.lastname: Srinivasan
authors.forename: M E
authors.initials: ME
authors.lastname: van der Pluijm
authors.forename: L J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: T J
authors.initials: TJ
authors.lastname: Visser
authors.forename: E P
authors.initials: EP
authors.lastname: Krenning
mesh_terms: D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D007205:Indium Radioisotopes / Q000493:pharmacokinetics*; D008297:Male; D004369:Pentetic Acid / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D011917:Rats, Inbred Lew; D018004:Receptors, Bombesin / Q000819:agonists*; D014018:Tissue Distribution
chemical_list: C400044:DTPA-Pro(1),Tyr(4)bombesin; D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D004369:Pentetic Acid; D001839:Bombesin