Targeting of a CCK2 receptor splice variant with 111In-labelled cholecystokinin-8 (CCK8) and 111In-labelled minigastrin

Peter Laverman, Susan Roosenburg, Martin Gotthardt, Jeseong Park, Wim J G Oyen, Marion De Jong, Mark Hellmich, Floris P J T Rutjes, Floris L. Van Delft, Otto C. Boerman

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Purpose: Radiolabelled cholecystokinin (CCK) and gastrin-derived peptides potentially can be used for peptide receptor radionuclide therapy (PRRT). Recently, a splice variant version of the CCK2R has been identified, designated CCK2i4svR. Constitutive expression of this receptor has been demonstrated in human colorectal cancer and in pancreatic cancer, but not in normal tissue. So far, it has never been shown whether radiolabelled peptides can target the CCK2i4svR in vivo. In this paper, we investigated the potential of sulfated 111In-labelled DOTA-CCK8 (sCCK8), a pan-CCKR-binding peptide, and [111In]DOTA-minigastrin (MG0), a CCK2R selective peptide, for the targeting of the CCK2i4svR. Materials and methods: The receptor binding affinity of [111In]DOTA-sCCK8 and [111In]DOTA-MG0 for the CCK2R and CCK2i4svR was determined using stably transfected HEK293 cell lines, expressing either CCK2R or CCK2i4svR. Tumour targeting was studied in HEK293-CCK2i4svR tumour-bearing athymic mice. Results: [111In]DOTA- sCCK8 as well as [111In]DOTA-MG0 specifically bound both CCK2R and CCK2i4svR with affinities in the low nanomolar range. In vivo experiments revealed that accumulation of both peptides in CCK2i4svR-positive tumours was similar (3.21±0.77 and 3.01±0.67%ID/g, sCCK8 and MG0, respectively, 24 h p.i.). Kidney retention of [111In]DOTA-MG0 (32.4±7.5%ID/g, 24 h p.i.) was markedly higher than that of [ 111In]DOTA-sCCK8 (2.75±0.31%ID/g, 24 h p.i.). Conclusion: We demonstrated that the CCK2i4svR is a potential target for PRRT using a radiolabelled sulfated CCK8 peptide. As this receptor is expressed on colorectal and pancreatic tumours, but not in normal tissue, these tumours are potentially new targets for PRRT with CCK8 and gastrin analogs.

Original languageEnglish (US)
Pages (from-to)386-392
Number of pages7
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume35
Issue number2
DOIs
StatePublished - Feb 2008

Fingerprint

Cholecystokinin B Receptor
Peptides
Peptide Receptors
Radioisotopes
Gastrins
Colorectal Neoplasms
Neoplasms
indium-111-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
minigastrin
cholecystokinin 8
HEK293 Cells
Cholecystokinin
Pancreatic Neoplasms
Nude Mice
Therapeutics
Kidney
Cell Line

Keywords

  • CCK8
  • Cholecystokinin-2 receptor
  • Cholecystokinin-2 splice variant receptor
  • Minigastrin
  • Peptide receptor radionuclide therapy (PRRT)

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology

Cite this

Targeting of a CCK2 receptor splice variant with 111In-labelled cholecystokinin-8 (CCK8) and 111In-labelled minigastrin. / Laverman, Peter; Roosenburg, Susan; Gotthardt, Martin; Park, Jeseong; Oyen, Wim J G; De Jong, Marion; Hellmich, Mark; Rutjes, Floris P J T; Van Delft, Floris L.; Boerman, Otto C.

In: European Journal of Nuclear Medicine and Molecular Imaging, Vol. 35, No. 2, 02.2008, p. 386-392.

Research output: Contribution to journalArticle

Laverman, P, Roosenburg, S, Gotthardt, M, Park, J, Oyen, WJG, De Jong, M, Hellmich, M, Rutjes, FPJT, Van Delft, FL & Boerman, OC 2008, 'Targeting of a CCK2 receptor splice variant with 111In-labelled cholecystokinin-8 (CCK8) and 111In-labelled minigastrin', European Journal of Nuclear Medicine and Molecular Imaging, vol. 35, no. 2, pp. 386-392. https://doi.org/10.1007/s00259-007-0604-1
Laverman, Peter ; Roosenburg, Susan ; Gotthardt, Martin ; Park, Jeseong ; Oyen, Wim J G ; De Jong, Marion ; Hellmich, Mark ; Rutjes, Floris P J T ; Van Delft, Floris L. ; Boerman, Otto C. / Targeting of a CCK2 receptor splice variant with 111In-labelled cholecystokinin-8 (CCK8) and 111In-labelled minigastrin. In: European Journal of Nuclear Medicine and Molecular Imaging. 2008 ; Vol. 35, No. 2. pp. 386-392.
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abstract = "Purpose: Radiolabelled cholecystokinin (CCK) and gastrin-derived peptides potentially can be used for peptide receptor radionuclide therapy (PRRT). Recently, a splice variant version of the CCK2R has been identified, designated CCK2i4svR. Constitutive expression of this receptor has been demonstrated in human colorectal cancer and in pancreatic cancer, but not in normal tissue. So far, it has never been shown whether radiolabelled peptides can target the CCK2i4svR in vivo. In this paper, we investigated the potential of sulfated 111In-labelled DOTA-CCK8 (sCCK8), a pan-CCKR-binding peptide, and [111In]DOTA-minigastrin (MG0), a CCK2R selective peptide, for the targeting of the CCK2i4svR. Materials and methods: The receptor binding affinity of [111In]DOTA-sCCK8 and [111In]DOTA-MG0 for the CCK2R and CCK2i4svR was determined using stably transfected HEK293 cell lines, expressing either CCK2R or CCK2i4svR. Tumour targeting was studied in HEK293-CCK2i4svR tumour-bearing athymic mice. Results: [111In]DOTA- sCCK8 as well as [111In]DOTA-MG0 specifically bound both CCK2R and CCK2i4svR with affinities in the low nanomolar range. In vivo experiments revealed that accumulation of both peptides in CCK2i4svR-positive tumours was similar (3.21±0.77 and 3.01±0.67{\%}ID/g, sCCK8 and MG0, respectively, 24 h p.i.). Kidney retention of [111In]DOTA-MG0 (32.4±7.5{\%}ID/g, 24 h p.i.) was markedly higher than that of [ 111In]DOTA-sCCK8 (2.75±0.31{\%}ID/g, 24 h p.i.). Conclusion: We demonstrated that the CCK2i4svR is a potential target for PRRT using a radiolabelled sulfated CCK8 peptide. As this receptor is expressed on colorectal and pancreatic tumours, but not in normal tissue, these tumours are potentially new targets for PRRT with CCK8 and gastrin analogs.",
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T1 - Targeting of a CCK2 receptor splice variant with 111In-labelled cholecystokinin-8 (CCK8) and 111In-labelled minigastrin

AU - Laverman, Peter

AU - Roosenburg, Susan

AU - Gotthardt, Martin

AU - Park, Jeseong

AU - Oyen, Wim J G

AU - De Jong, Marion

AU - Hellmich, Mark

AU - Rutjes, Floris P J T

AU - Van Delft, Floris L.

AU - Boerman, Otto C.

PY - 2008/2

Y1 - 2008/2

N2 - Purpose: Radiolabelled cholecystokinin (CCK) and gastrin-derived peptides potentially can be used for peptide receptor radionuclide therapy (PRRT). Recently, a splice variant version of the CCK2R has been identified, designated CCK2i4svR. Constitutive expression of this receptor has been demonstrated in human colorectal cancer and in pancreatic cancer, but not in normal tissue. So far, it has never been shown whether radiolabelled peptides can target the CCK2i4svR in vivo. In this paper, we investigated the potential of sulfated 111In-labelled DOTA-CCK8 (sCCK8), a pan-CCKR-binding peptide, and [111In]DOTA-minigastrin (MG0), a CCK2R selective peptide, for the targeting of the CCK2i4svR. Materials and methods: The receptor binding affinity of [111In]DOTA-sCCK8 and [111In]DOTA-MG0 for the CCK2R and CCK2i4svR was determined using stably transfected HEK293 cell lines, expressing either CCK2R or CCK2i4svR. Tumour targeting was studied in HEK293-CCK2i4svR tumour-bearing athymic mice. Results: [111In]DOTA- sCCK8 as well as [111In]DOTA-MG0 specifically bound both CCK2R and CCK2i4svR with affinities in the low nanomolar range. In vivo experiments revealed that accumulation of both peptides in CCK2i4svR-positive tumours was similar (3.21±0.77 and 3.01±0.67%ID/g, sCCK8 and MG0, respectively, 24 h p.i.). Kidney retention of [111In]DOTA-MG0 (32.4±7.5%ID/g, 24 h p.i.) was markedly higher than that of [ 111In]DOTA-sCCK8 (2.75±0.31%ID/g, 24 h p.i.). Conclusion: We demonstrated that the CCK2i4svR is a potential target for PRRT using a radiolabelled sulfated CCK8 peptide. As this receptor is expressed on colorectal and pancreatic tumours, but not in normal tissue, these tumours are potentially new targets for PRRT with CCK8 and gastrin analogs.

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KW - CCK8

KW - Cholecystokinin-2 receptor

KW - Cholecystokinin-2 splice variant receptor

KW - Minigastrin

KW - Peptide receptor radionuclide therapy (PRRT)

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