Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors

Targeting neuroendocrine tumors expressing somatostatin receptor subtypes (sst) with radiolabeled somatostatin agonists is an established diagnostic and therapeutic approach in oncology. While agonists readily internalize into tumor cells, permitting accumulation of radioactivity, radiolabeled antagonists do not, and they have not been considered for tumor targeting. The macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was coupled to two potent somatostatin receptor-selective peptide antagonists [NH(2)-CO-c(DCys-Phe-Tyr-DAgl(8)(Me,2-naphthoyl)-Lys-Thr-Phe-Cys)-OH (sst(3)-ODN-8) and a sst(2)-selective antagonist (sst(2)-ANT)], for labeling with (111/nat)In. (111/nat)In-DOTA-sst(3)-ODN-8 and (111/nat)In-DOTA-[4-NO(2)-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH(2)] ((111/nat)In-DOTA-sst(2)-ANT) showed high sst(3)- and sst(2)-binding affinity, respectively. They did not trigger sst(3) or sst(2) internalization but prevented agonist-stimulated internalization. (111)In-DOTA-sst(3)-ODN-8 and (111)In-DOTA-sst(2)-ANT were injected intravenously into mice bearing sst(3)- and sst(2)-expressing tumors, and their biodistribution was monitored. In the sst(3)-expressing tumors, strong accumulation of (111)In-DOTA-sst(3)-ODN-8 was observed, peaking at 1 h with 60% injected radioactivity per gram of tissue and remaining at a high level for >72 h. Excess of sst(3)-ODN-8 blocked uptake. As a control, the potent agonist (111)In-DOTA-[1-Nal(3)]-octreotide, with strong sst(3)-binding and internalization properties showed a much lower and shorter-lasting uptake in sst(3)-expressing tumors. Similarly, (111)In-DOTA-sst(2)-ANT was injected into mice bearing sst(2)-expressing tumors. Tumor uptake was considerably higher than with the highly potent sst(2)-selective agonist (111)In-diethylenetriaminepentaacetic acid-[Tyr(3),Thr(8)]-octreotide ((111)In-DTPA-TATE). Scatchard plots showed that antagonists labeled many more sites than agonists. Somatostatin antagonist radiotracers therefore are preferable over agonists for the in vivo targeting of sst(3)- or sst(2)-expressing tumors. Antagonist radioligands for other peptide receptors need to be evaluated in nuclear oncology as a result of this paradigm shift.

Die ostafrikanischen Inseln

von C. Keller

National silicosis conference ... : Final report[s] of the committee[s].

List of references in parts 1 and 2.

Cast iron pipe /

Copy in Dept. of Rare Books and Special Collections bound in original black leather stamped in gold. P. 9-10 lacking.

Annual report of the State Inspector of Apiaries.

WI docs no.: API.1:1902 -1914

Bark beetles and ambrosia beetles (Coleoptera: Scolytoidea): with special references to species occurring in North Carolina,

Bibliography: p. [162]-167.

Geology of parts of the upper Mississippi Valley zinc-lead district.

Issued as separate chapters A-I.

The works of Robert G. Ingersoll.

vol. 13 has imprint date 1911.

Statistisk tabelværk.

Issued in 5 raekke (pub. 1898?-1960): litra A [Industry. Vital Statistics] no. 1-24. 1899-1948; litra B [Legal statistics. Crime] no. 1- 1898- ; litra C [Agriculture] no. 1- 1898- ; litra D [Commerce. Foreign trade] no. 1-79. 1898-1958; litra E [Finance] no. 1-25. 1902-1956.

The care and maintenance of pumps and water systems.

Mode of access: Internet.

Vitamin B1 (Thiamine hydochloride); annotated bibliography. Supplement 1942.

Reproduced from typewritten copy.

The works of Robert G. Ingersoll.

Added t.-p. engraved: The writings of Robert G. Ingersoll.

A soldier in two armies,

Life of Charles Abraham Hart, who served in Company I, 6th Mass. infantry in Porto Rico.

Condensers and auxiliaries. 1914 /

Mode of access: Internet.

In the ranks: from the Wilderness to Appomattox court-house.

Mode of access: Internet.