title: Synthesis, Characterization, and In Vitro Evaluation of New (99m)Tc/Re(V)-Cyclized Octreotide Analogues: An Experimental and Computational Approach.
abstract: Radiolabeled proteolytic degradation-resistant somatostatin analogues have been of long-standing interest as cancer imaging and radiotherapy agents for targeting somatostatin receptor-positive tumors. Our interest in developing (186)Re- and (188)Re-based therapeutic radiopharmaceuticals led to investigation of a new Re(V)-cyclized octreotide analogue, Re(V)-cyclized, thiolated-DPhe(1)-Cys(2)-Tyr(3)-DTrp(4)-Lys(5)-Thr(6)-Cys(7)-Thr(OH)(8) (Re-SDPhe-TATE) using both experimental and quantum chemical methods. The metal is directly coordinated to SDPhe-TATE through cyclization of the peptide around the [ReO](3+) core. Upon complexation, four isomers were observed; the isolated/semi-isolated isomers exhibited different somatostatin receptor (sstr) binding affinities, 0.13 to 1.5 μM, in rat pancreatic tumor cells. Two-dimensional NMR experiments and electronic structure calculations were employed to elucidate the structural differences among the different isomers. According to NMR studies, the metal is coordinated to three thiolates and the backbone amide of Cys(2) in isomers 1 and 4, whereas the metal is coordinated to three thiolates and the backbone amide of Tyr(3) in isomer 2. Quantum chemical methods clarified the stereochemistry of Re-SDPhe-TATE and the possible peptide arrangements around the [ReO](3+) core. The re-cyclization reaction was translated to the (99m)Tc radiotracer level with four isomers observed on complexation with comparable HPLC retention times as the Re-SDPhe-TATE isomers. About 85% total (99m)Tc labeling yield was achieved by ligand exchange from (99m)Tc-glucoheptonate at 60 °C for an hour. About 100% and 51% of (99m)Tc(V)-cyclized SDPhe-TATE remained intact in phosphate buffered saline and 1 mM cysteine solution under physiological conditions at 6 h, respectively.
authors.forename: Yawen
authors.initials: Y
authors.lastname: Li
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri 65201, United States.
authors.forename: Lixin
authors.initials: L
authors.lastname: Ma
authors.forename: Vikram
authors.initials: V
authors.lastname: Gaddam
authors.forename: Fabio
authors.initials: F
authors.lastname: Gallazzi
authors.affiliation: University of Missouri Research Reactor Center , Columbia, Missouri 65211, United States.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Hennkens
authors.forename: Michael
authors.initials: M
authors.lastname: Harmata
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, Missouri 65201, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lewis
authors.forename: Carol A
authors.initials: CA
authors.lastname: Deakyne
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Jurisson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D008968:Molecular Conformation; D015282:Octreotide / Q000737:chemistry*; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011789:Quantum Theory; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors; D012211:Rhenium / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; D012211:Rhenium; D015282:Octreotide