Labelling and evaluation of new stabilised neurotensin (8-13) analogues for single photon emission tomography (SPET)

Abstract

Neurotensin(8–13) analogues were biologically stabilised by replacement of the peptide bond between amino acids 8 and 9 by the reduced ψ(CH2‐NH) isostere. Diethylenetriaminepentaacetic acid (DTPA) analogues for In‐111 labelling and 2‐bromo‐phenyl‐acetyl analogues for radioiodination, showed receptor affinities in the nanomolar range in combination with a biological half life in human plasma up to 275 minutes. Biodistribution studies in male Wistar rats of metabolically stabilised and non‐stabilised 111In‐DTPA‐NT(8–13) analogues showed a major clearance from the blood through the kidneys. 125I‐Labelled neurotensin (8–13) analogues showed accumulation up to 2.2% of the injected dose per g tissue in the liver which might be an important disadvantage when diagnosis of tumours in the gut is aimed. Neurotensin(8–13) analogues labelled with In‐111 or I‐123 may act as new potential peptidergic radiopharmaceuticals for SPET diagnosis of neurotensin receptor (NTR) positive tumours. Copyright © 1999 John Wiley & Sons, Ltd.

Radiopharmaceuticals for imaging and endoradiotherapy of neurotensin receptor‐positive tumors

“…One of the first NT analogs labeled with the SPECT nuclide Tc-99m and with Re-188 as a therapeutic surrogate was reported by Chavatte et al almost 20 years ago. 13,14 In that study, the chelator dimethyl-Gly-Ser-Cys(acetamidomethyl)-Gly (RP414) was bound to 4 different NT derivatives with variations in Arg 8 -Arg 9 by systematic exchange with Lys (entry 1, Table 1). The biological half-lives in human plasma of the 4 peptides (Continues) in vitro were determined to be 20 to 30 minutes, and all 4 peptides maintained high affinity for NTS1, 13 indicating that modifications at Arg-Arg are well tolerated regarding NTS1 binding affinity.…”

“…One of the first NT(8-13) derivatives radiolabeled with In-111 and with I-123, both of which are radioisotopes suitable for SPECT imaging, was reported in 1998 to 1999. 14,31 Different NT(8-13) derivatives were synthesized with a focus on the Arg-Arg bond in order to enhance metabolic stability and receptor affinity. 32 Therefore, Lys-for-Arg exchanges were conducted with or without an additional reduction of the amide bond between the 2 amino acids.…”

“…One of the first NT analogs labeled with the SPECT nuclide Tc‐99m and with Re‐188 as a therapeutic surrogate was reported by Chavatte et al almost 20 years ago . In that study, the chelator dimethyl‐Gly‐Ser‐Cys(acetamidomethyl)‐Gly (RP414) was bound to 4 different NT derivatives with variations in Arg 8 ‐Arg 9 by systematic exchange with Lys (entry 1, Table ).…”

“…The radiolabeling was achieved by incorporating the In‐111 chelator DTPA (diethylenetriaminepentaacetic acid) at the N‐terminus. All derivatives showed high receptor affinities, and for DTPA‐Lys‐Ψ(CH 2 NH)‐Arg‐Pro‐Tyr‐Ile‐Leu, a significantly elongated half‐life in human plasma in vitro (t 1/2 = 275 vs 10 minutes for the unmodified DTPA‐NT(8–13)) was determined (entries 1 and 2, Table ) …”

A novel tetrabranched neurotensin(8–13) cyclam derivative: Synthesis, 64Cu-labeling and biological evaluation

“…Most radiopharmaceutical investigations have been performed with the hexapeptide (Arg 8 -Arg 9 -Pro 10 -Tyr 11 -Ile 12 -Leu 13 ) NT(8-13)-the shortest neurotensin binding motif for efficient and selective ligand-receptor interaction-and their metabolic stabilized derivatives [21]. These monomeric neurotensin fragments have been mainly radiolabeled with 99m Tc, but also to a lesser extent with 111 In, 125 I, 177 Lu, 188 Re, 201 Tl and 18 F [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. Hitherto, radiolabeling of neurotensin with 64 Cu has not been reported.…”