In vitro structure–activity relationship of Re-cyclized octreotide analogues

Dannoon, Shorouk; Hennkens, Heather M.; Ma, Lixin; Gallazzi, Fabio; Lewis, Michael R.; Jurisson, Silvia S.

doi:10.1016/j.nucmedbio.2010.03.008

Cited by 7 publications

(34 citation statements)

References 30 publications

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“…Compounds 1 – 6 are derivatives of the TATE sequence, and we recently described their Re-cyclized analogues. [13, 14] The synthesis and use of 99m Tc-TATE was previously reported,[9] however it was repeated herein for direct comparison under the same in vitro conditions as the 99m Tc-cyclized products of TATE derivatives 1 through 6 .…”

Section: Resultsmentioning

confidence: 99%

“…[13, 14] The linear peptides were purified by semi-preparative RP-HPLC using a multi-step gradient to separate the desired products from the impurities present in the crude sample. The collected fractions, shown to be pure by LC-ESI-MS characterization, were combined, lyophilized and stored at −20 °C.…”

Section: Methodsmentioning

confidence: 99%

“…The reaction was heated at 60 °C for 30 min following pH adjustment to 7.9–8.1 using 0.1 M NaOH. The formation of the desired 99m Tc-cyclized peptides was confirmed by RP-HPLC co-injection and co-elution of the isolated 99m Tc-products with their non-radioactive Re-cyclized analogues,[13, 14] based on retention times using two detectors (UV and NaI(Tl)). The collected purified fractions were combined with 1–2 mg of gentisic acid, concentrated by centrifugal evaporation for 30 min to ensure removal of the organic solvent components, and diluted in a solvent appropriate for either in vitro stability or in vivo biodistribution studies.…”

Section: Methodsmentioning

confidence: 99%

“…[13] The modifications made to the TATE sequence were designed to tighten metal coordination and distance the metal center from the SSTR pharmacophore, in an effort to increase the affinity for SSTR2 (from an IC 50 of 29 nM for Re-TATE, [14]) and to improve the stability of the peptide metal center (in vitro and in vivo instability were observed at the radiotracer level for 99m Tc-TATE, [9]). Though the modifications resulted in a number of Re metal center coordination modes, none of the other Re-cyclized TATE derivatives demonstrated SSTR2 affinities in the nanomolar range.…”

Section: Introductionmentioning

confidence: 99%

“…In this paper, the results of in vitro stability studies of six TATE-based peptide sequences radiolabeled with 99m Tc, which are analogous to six of the Re-cyclized peptides we previously reported,[13, 14] will be discussed. The studies presented herein explore the effects of TATE sequence modifications on 99m Tc radiolabeling and in vitro stability, and thereby complement our macroscopic, nonradioactive Re-cyclized peptide studies.…”

Section: Introductionmentioning

confidence: 99%

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Labeling, stability and biodistribution studies of 99mTc-cyclized Tyr3-octreotate derivatives

Hennkens

Dannoon

Noll

et al. 2011

Nuclear Medicine and Biology

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Introduction-To probe the interplay between radiotracer stability and somatostatin receptor affinity, Tyr 3 -octreotate and six variations of its peptide sequence, for which the Re-cyclized products were previously reported, were radiolabeled with 99m Tc and investigated for their in vitro stability.Methods-Radiolabeling of the peptides was effected by ligand exchange from 99m Tcglucoheptonate, and the desired products were purified by radio-RP-HPLC. The in vitro stability in phosphate-buffered saline, mouse serum, and cysteine solutions at physiological temperature and pH for all seven 99m Tc-cyclized peptides was determined by radio-RP-HPLC and radio-TLC. Normal CF-1 mouse biodistribution studies were performed for three of the 99m Tc-cyclized peptides.Results-Based on the fully characterized Re-cyclized peptide analogues, four 99m Tccoordination motifs were proposed for the 99m Tc-cyclized peptides. Technetium-99m-cyclized Tyr 3 -octreotate derivatives with N 2 S 2 metal coordination modes and large metal ring sizes were susceptible to oxidation and loss of 99m Tc in the form of 99m TcO 4 − , as evidenced by their instability in the various solutions under physiological conditions (15-58% intact at 24 h). As anticipated, the addition of a third cysteine to the sequence stabilized the 99m Tc metal coordination, and peptides with NS 3 coordination modes remained >85% intact out to 24 h. No significant differences were observed in the biodistribution studies performed with three peptides of varying stabilities.Conclusions-Improvements in stability were not sufficient to outweigh the low somatostatin receptor affinity for the peptides in this study. Further improvements in the peptide sequence and/ or metal coordination are needed to result in a radiodiagnostic/radiotherapeutic pair for targeting the somatostatin receptor.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Labeling, stability and biodistribution studies of 99mTc-cyclized Tyr3-octreotate derivatives

Hennkens

Dannoon

Noll

et al. 2011

Nuclear Medicine and Biology

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^99m Tc Radiopharmaceutical Chemistry

Papagiannopoulou¹

2020

Handbook of Radiopharmaceuticals

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Using potential energy surface scans to examine the bond dissociation energies of trans-ReOS2N2 and [ReOS3N]1− model complexes

Kreuer

Demoin

et al. 2014

Computational and Theoretical Chemistry

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Developing Re(V)-based therapeutic agents, where the ReO 3+ core is coordinated to a multidentate ligand, is of interest in the radiopharmaceutical sciences because of the desirable nuclear properties of 186 Re/ 188 Re. A reliable yet cost-effective computational method for evaluating the strength of each coordination bond while preserving the integrity of the metal-ligand complex would provide quantitative input for ligand design. A relaxed potential energy surface (PES) scan approach is assessed for trans-ReO(SH) 2 (NH 2)(NH 3), [ReO(SH) 3 (NH 2)] 1-, and [ReO(SH) 3 (N(H)CHO)] 1model complexes to calculate bond dissociation energies (BDEs) for Re-NH 3 , Re-NH 2 , Re-N(H)CHO and Re-SH bonds, common components of Re(V) coordination environments. The PES scans were performed using various combinations of DFT/coupled-cluster methods and basis sets, and the effect of bulk solvent was examined by using the integral equation formalism of the polarizable continuum model (IEF-PCM). BDEs obtained from the PES scans are compared to those obtained for infinite separation. In the gas phase, the BDE curves reach about 90% of the total BDE at 2 Å and plateau by 3.0 to 3.5 Å beyond the equilibrium bond length; in the presence of implicit solvent, the BDE water curves plateau at a shorter distance and more than 90% of the total BDE is recovered at 2 Å. The gas-phase PES scans follow the desired reaction coordinate for NH 3 , [N(H)CHO] 1and SH 1-, but not for the poor leaving group NH 2 1-. The desired heterolytic cleavage of the Re-NH 2 bond is achieved when the PES scans are performed in the presence of solvent. Elongating the Re-S/N bonds in a rigid, multidentate trans-ReO-N 2 S 2 complex yields BDE trends similar to those found for the model complexes (Re-NH 2 > Re-N(H)CHO > Re-SH > Re-NH 3).

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In vitro structure–activity relationship of Re-cyclized octreotide analogues

Cited by 7 publications

References 30 publications

Labeling, stability and biodistribution studies of 99mTc-cyclized Tyr3-octreotate derivatives

Labeling, stability and biodistribution studies of 99mTc-cyclized Tyr3-octreotate derivatives

^99m Tc Radiopharmaceutical Chemistry

Using potential energy surface scans to examine the bond dissociation energies of trans-ReOS2N2 and [ReOS3N]1− model complexes

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