Effect of a spacer moiety on radiometal labelled Neurotensin derivatives

Mascarin, Alba; Valverde, Ibai E.; Mindt, Thomas L.

doi:10.1524/ract.2013.2090

Cited by 5 publications

(12 citation statements)

References 19 publications

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“…We previously reported that the introduction of a hydrophilic spacer made of a tetraethylene glycol (PEG 4 ) moiety between the tumor‐targeting peptide NT(8–13) and the radiometal complex based on the universal macrocyclic chelator 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) improves the cell‐internalization properties, receptor affinity, and metabolic stability of conjugate NT 1 (Table and Figures –) . Therefore, we used the general structure NT 2 as a reference for further investigations of the effect of amino acid substitutions on the peptide sequence NT(8–13).…”

Section: Resultssupporting

confidence: 92%

“…[a] Calculated values. [b] Observed ESI‐HRMS data: [ M +2 H + ] 2+ ; preliminary data on compounds NT‐1 , 2 , and 3 were reported previously …”

Section: Resultsmentioning

confidence: 99%

“…NT(8–13) derivatives NT 1 – 6 were radiolabeled by procedures previously described . In brief, peptide conjugates were used as stock solutions of 1 mg mL −1 in H 2 O.…”

Section: Methodsmentioning

confidence: 99%

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Structure–Activity Relationship Studies of Amino Acid Substitutions in Radiolabeled Neurotensin Conjugates

2015

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Radiolabeled derivatives of the peptide neurotensin (NT) and its binding sequence NT(8-13) have been studied as potential imaging probes and therapeutics for NT-1-receptor-positive cancer. However, a direct comparison of reported NT analogues, even if radiolabeled with the same radionuclide, is difficult because different techniques and models have been used for preclinical evaluations. In an effort to identify a suitable derivative of NT(8-13) for radiotracer development, we herein report a side-by-side in vitro comparison of radiometallated NT derivatives bearing some of the most commonly reported amino acid substitutions in their sequence. Performed investigations include cell internalization experiments, determinations of receptor affinity, measurements of the distribution coefficient, and blood serum stability studies. Of the [(177)Lu]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-labeled examples studied, analogues of NT(8-13) containing a short hydrophilic tetraethylene glycol (PEG4 ) spacer between the peptide and the radiometal complex, and a minimum number of substitutions of amino acid residues, exhibited the most promising properties in vitro.

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Section: Resultssupporting

confidence: 92%

“…[a] Calculated values. [b] Observed ESI‐HRMS data: [ M +2 H + ] 2+ ; preliminary data on compounds NT‐1 , 2 , and 3 were reported previously …”

Section: Resultsmentioning

confidence: 99%

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Structure–Activity Relationship Studies of Amino Acid Substitutions in Radiolabeled Neurotensin Conjugates

2015

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“…To date, NTR1-targeted peptides have been labeled with a number of clinically relevant radiometals, such as 99m Tc, 111 In and 68 Ga[11,15,21–23]. In recent years, 177 Lu, a theranostic radioisotope, has received increasing attention for potential clinical applications due to its dual emission characteristics[24–27].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of DOTA-chelated neurotensin analogs with spacer-enhanced biological performance for neurotensin-receptor-1-positive tumor targeting

Jia

Shi

Zhou

et al. 2015

Nuclear Medicine and Biology

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Introduction Neurotensin receptor 1 (NTR1) is overexpressed in many cancers types. Neurotensin (NT), a 13 amino acid peptide, is the native ligand for NTR1 and exhibits high (nM) affinity to the receptor. Many laboratories have been investigating the development of diagnostic and therapeutic radiopharmaceuticals for NTR1-positive cancers based on the NT peptide. To improve the biological performance for targeting NTR1, we proposed NT analogs with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelation system and different lengths of spacers. Methods We synthesized four NTR1-targeted conjugates with spacer lengths from 0 to 9 atoms (null (N0), β-Ala-OH (N1), 5-Ava-OH (N2), and 8-Aoc-OH (N3)) between the DOTA and the pharmacophore. In vitro competitive binding, internalization and efflux studies were performed on all four NT analogs. Based on these findings, metabolism studies were carried out on our best performing conjugate, 177Lu-N1. Lastly, in vivo biodistribution and SPECT/CT imaging studies were performed using 177Lu-N1 in an HT-29 xenograft mouse model. Results As shown in competitive binding assay, the NT analogs with different spacers (N1, N2 and N3) exhibited lower IC50 values than the NT analog without a spacer (N0). Furthermore, N1 revealed higher retention in HT-29 cells with more rapid internalization and slower efflux than the other NT analogs. In vivo biodistribution and SPECT/CT imaging studies of 177Lu-N1 demonstrated excellent accumulation (3.1 ± 0.4 %ID/g) in the NTR1-positive tumors at 4 h post-administration. Conclusions The DOTA chelation system demonstrated some modest steric inhibition of the pharmacophore. However, the insertion of a 4-atom hydrocarbon spacer group restored optimal binding affinity of the analog. The in vivo assays indicated that 177Lu-N1 could be used for imaging and radiotherapy of NTR1-positive tumors.

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“…In this study, the NT‐XIX peptide was labeled with rhenium‐188 (half‐life of 17.0 hours, β‐energy of 2.12 MeV) by forming the 188 Re‐tricarbonyl complex, as already mentioned in the above chapter concerning Tc‐99m (entry 10, Table ). The first peptides labeled with Lu‐177 were reported by the Mindt group, who investigated the effect of different spacers (X), such as Ahx (aminohexanoic acid) and PEG 4 (tetraethylene glycol), on the physicochemical properties of a small series of peptides (entry 1, Table ) with a specific focus on the impacts on lipophilicity, stability in vitro in serum, and receptor affinity and internalization . Most importantly, the peptide with the PEG 4 ‐spacer linked to the DOTA chelator was found to have a more favorable receptor affinity by a factor of 4 compared with NT(8–13) without the spacer, and the presence of the spacer did not significantly affect the lipophilicity of the peptide.…”

Section: Introductionmentioning

confidence: 99%

Radiopharmaceuticals for imaging and endoradiotherapy of neurotensin receptor‐positive tumors

Maschauer

Prante

2018

Labelled Comp Radiopharmac

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The neurotensin receptors are overexpressed in various tumor types, especially in highly progressive pancreatic tumors. As this cancer has a poor 5-year survival prognosis, there is an urgent need to improve early diagnosis and treatment strategies. This review article provides an overview of the latest developments in radiopharmaceuticals for neurotensin receptor-positive tumors, including peptidic and non-peptidic radiopharmaceuticals, not only for SPECT and PET but also for endoradiotherapy.

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Effect of a spacer moiety on radiometal labelled Neurotensin derivatives

Cited by 5 publications

References 19 publications

Structure–Activity Relationship Studies of Amino Acid Substitutions in Radiolabeled Neurotensin Conjugates

Structure–Activity Relationship Studies of Amino Acid Substitutions in Radiolabeled Neurotensin Conjugates

Evaluation of DOTA-chelated neurotensin analogs with spacer-enhanced biological performance for neurotensin-receptor-1-positive tumor targeting

Radiopharmaceuticals for imaging and endoradiotherapy of neurotensin receptor‐positive tumors

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