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Synthesis of BVD15 Peptide Analogues as Models for Radioligands in Tumour Imaging

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International Journal of Peptide Research and Therapeutics Aims and scope Submit manuscript

Abstract

Neuropeptide Y (NPY) Y1 receptors are overexpressed in human breast carcinomas. They also have important functional roles in breast tumour growth and metastasis. This study investigates the synthesis of 15 truncated NPY analogues as models for Y1 receptor specific radiopharmaceuticals, using competition radioreceptor binding assays from brain tissue homogenates from Y2Y4-double knockout mice. These peptides are based on the previously reported BVD15 scaffold. Different measures to improve Y1 affinity and plasma metabolic stability were investigated. Extending from the previously reported [Lys(DOTA)4]BVD15 analogue, it was found that lysine4 is capable of tolerating various modifications, including prosthetic groups and other bifunctional chelators, but also that [Lys4]BVD15 has improved Y1 affinity, relative to BVD15 itself. Substitution of lysine4 for side chain shortened analogues retains Y1 receptor affinity of the analogues. Furthermore, modifications at the N-terminal isoleucine resulted in dramatic reduction of Y1 affinity.

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Abbreviations

Ac:

Acetyl

Arg:

Arginine

Asn:

Asparagine

BFC:

Bifunctional chelator

Bn:

Benzyl

Dab:

2,4-Diaminobutyric acid

Dap:

2,3-Diaminopropionic acid

DIC:

N,N-Diisopropylcarbodiimide

DIPEA:

N,N-Diisopropylethylamine

DMB:

1,3-Dimethoxybenzene

DMF:

N,N-Dimethylformamide

DOTA:

1,4,7,10-Tetraazacyclododecanetetraacetic acid

FBz:

4-Fluorobenzoic acid

Fmoc:

Fluorenylmethyloxycarbonyl

HOBt:

N-Hydroxybenzotriazole

HCTU:

O-(6-Chloro-1-hydrocibenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

HFIP:

1,1,1,3,3,3-Hexafluoroisopropanol

IBz:

4-Iodobenzoic acid

Ile:

Isoleucine

Leu:

Leucine

Lys:

Lysine

NCS:

Isothiocyanate

NOTA:

1,4,7-Triazacyclononanetriacetic acid

NPY:

Neuropeptide Y

Orn:

Ornithine

Pro:

Proline

RP-HPLC:

Reverse phase high performance liquid chromatography

TFA:

Trifluoroacetic acid

TIPS:

Triisopropylsilane

Tyr:

Tyrosine

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Acknowledgments

We sincerely thank CRC for Biomedical Imaging Development (CRCBID) for funding this project, and providing a post-graduate scholarship to ML.

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Authors and Affiliations

  1. Monash Institute of Pharmaceutical Sciences, 381 Royal Parade, Parkville, VIC, 3052, Australia

    Mengjie Liu, Simon J. Mountford & Philip E. Thompson

  2. Neuroscience Research Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, Darlinghurst, NSW, 2010, Australia

    Lei Zhang, I-Chieh Lee & Herbert Herzog

Authors
  1. Mengjie Liu
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  2. Simon J. Mountford
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  3. Lei Zhang
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  4. I-Chieh Lee
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  5. Herbert Herzog
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  6. Philip E. Thompson
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Corresponding author

Correspondence to Philip E. Thompson.

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Liu, M., Mountford, S.J., Zhang, L. et al. Synthesis of BVD15 Peptide Analogues as Models for Radioligands in Tumour Imaging. Int J Pept Res Ther 19, 33–41 (2013). https://doi.org/10.1007/s10989-012-9330-z

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  • DOI: https://doi.org/10.1007/s10989-012-9330-z

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