PET and SPECT imaging of a radiolabeled minigastrin analogue conjugated with DOTA, NOTA, and NODAGA and labeled with 64Cu, 68Ga, and 111In

S. Roosenburg; P. Laverman; L. Joosten; M. S. Cooper; P. K. Kolenc-Peitl; J. M. Foster; C. Hudson; J. Leyton; J. Burnet; W. J.G. Oyen; P. J. Blower; S. J. Mather; O. C. Boerman; J. K. Sosabowski

doi:10.1021/mp500283k

PET and SPECT imaging of a radiolabeled minigastrin analogue conjugated with DOTA, NOTA, and NODAGA and labeled with ⁶⁴Cu, ⁶⁸Ga, and ¹¹¹In

S. Roosenburg, P. Laverman^*, L. Joosten, M. S. Cooper, P. K. Kolenc-Peitl, J. M. Foster, C. Hudson, J. Leyton, J. Burnet, W. J.G. Oyen, P. J. Blower, S. J. Mather, O. C. Boerman, J. K. Sosabowski

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

73 Citations (Scopus)

Abstract

Cholecystokinin-2 (CCK-2) receptors, overexpressed in cancer types such as small cell lung cancers (SCLC) and medullary thyroid carcinomas (MTC), may serve as targets for peptide receptor radionuclide imaging. A variety of CCK and gastrin analogues has been developed, but a major drawback is metabolic instability or high kidney uptake. The minigastrin analogue PP-F11 has previously been shown to be a promising peptide for imaging of CCK-2 receptor positive tumors and was therefore further evaluated. The peptide was conjugated with one of the macrocyclic chelators DOTA, NOTA, or NODAGA. The peptide conjugates were then radiolabeled with either ⁶⁸Ga, ⁶⁴Cu, or ¹¹¹In. All (radio)labeled compounds were evaluated in vitro (IC₅₀) and in vivo (biodistribution and PET/CT and SPECT/CT imaging). IC₅₀ values were in the low nanomolar range for all compounds (0.79-1.51 nM). In the biodistribution studies, ⁶⁸Ga-and ¹¹¹In-labeled peptides showed higher tumor-to-background ratios than the ⁶⁴Cu-labeled compounds. All tested radiolabeled compounds clearly visualized the CCK2 receptor positive tumor in PET or SPECT imaging. The chelator did not seem to affect in vivo behavior of the peptide for ¹¹¹In-and ⁶⁸Ga-labeled peptides. In contrast, the biodistribution of the ⁶⁴Cu-labeled peptides showed high uptake in the liver and in other organs, most likely caused by high blood levels, probably due to dissociation of ⁶⁴Cu from the chelator and subsequent transchelation to proteins. Based on the present study, ⁶⁸Ga-DOTA-PP-F11 might be a promising radiopharmaceutical for PET/CT imaging of CCK2 receptor expressing tumors such as MTC and SCLC. Clinical studies are warranted to investigate the potential of this tracer.

Original language	English
Pages (from-to)	3930-3937
Number of pages	8
Journal	Molecular Pharmaceutics
Volume	11
Issue number	11
Early online date	3 Jul 2014
DOIs	https://doi.org/10.1021/mp500283k
Publication status	Published - 2014

Keywords

CCK2R peptide
Cu-64
DOTA
Ga-68
In-111
Macrocyclic chelator
NODAGA
NOTA
PET imaging

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/mp500283k

Cite this

Roosenburg, S., Laverman, P., Joosten, L., Cooper, M. S., Kolenc-Peitl, P. K., Foster, J. M., Hudson, C., Leyton, J., Burnet, J., Oyen, W. J. G., Blower, P. J., Mather, S. J., Boerman, O. C., & Sosabowski, J. K. (2014). PET and SPECT imaging of a radiolabeled minigastrin analogue conjugated with DOTA, NOTA, and NODAGA and labeled with ⁶⁴Cu, ⁶⁸Ga, and ¹¹¹In. Molecular Pharmaceutics, 11(11), 3930-3937. https://doi.org/10.1021/mp500283k

@article{deb3bd83681f4c6ba328f2bdd0b1284d,

title = "PET and SPECT imaging of a radiolabeled minigastrin analogue conjugated with DOTA, NOTA, and NODAGA and labeled with 64Cu, 68Ga, and 111In",

abstract = "Cholecystokinin-2 (CCK-2) receptors, overexpressed in cancer types such as small cell lung cancers (SCLC) and medullary thyroid carcinomas (MTC), may serve as targets for peptide receptor radionuclide imaging. A variety of CCK and gastrin analogues has been developed, but a major drawback is metabolic instability or high kidney uptake. The minigastrin analogue PP-F11 has previously been shown to be a promising peptide for imaging of CCK-2 receptor positive tumors and was therefore further evaluated. The peptide was conjugated with one of the macrocyclic chelators DOTA, NOTA, or NODAGA. The peptide conjugates were then radiolabeled with either 68Ga, 64Cu, or 111In. All (radio)labeled compounds were evaluated in vitro (IC50) and in vivo (biodistribution and PET/CT and SPECT/CT imaging). IC50 values were in the low nanomolar range for all compounds (0.79-1.51 nM). In the biodistribution studies, 68Ga-and 111In-labeled peptides showed higher tumor-to-background ratios than the 64Cu-labeled compounds. All tested radiolabeled compounds clearly visualized the CCK2 receptor positive tumor in PET or SPECT imaging. The chelator did not seem to affect in vivo behavior of the peptide for 111In-and 68Ga-labeled peptides. In contrast, the biodistribution of the 64Cu-labeled peptides showed high uptake in the liver and in other organs, most likely caused by high blood levels, probably due to dissociation of 64Cu from the chelator and subsequent transchelation to proteins. Based on the present study, 68Ga-DOTA-PP-F11 might be a promising radiopharmaceutical for PET/CT imaging of CCK2 receptor expressing tumors such as MTC and SCLC. Clinical studies are warranted to investigate the potential of this tracer.",

keywords = "CCK2R peptide, Cu-64, DOTA, Ga-68, In-111, Macrocyclic chelator, NODAGA, NOTA, PET imaging",

author = "S. Roosenburg and P. Laverman and L. Joosten and Cooper, {M. S.} and Kolenc-Peitl, {P. K.} and Foster, {J. M.} and C. Hudson and J. Leyton and J. Burnet and Oyen, {W. J.G.} and Blower, {P. J.} and Mather, {S. J.} and Boerman, {O. C.} and Sosabowski, {J. K.}",

year = "2014",

doi = "10.1021/mp500283k",

language = "English",

volume = "11",

pages = "3930--3937",

journal = "Molecular Pharmaceutics",

issn = "1543-8384",

publisher = "American Chemical Society",

number = "11",

}

Roosenburg, S, Laverman, P, Joosten, L, Cooper, MS, Kolenc-Peitl, PK, Foster, JM, Hudson, C, Leyton, J, Burnet, J, Oyen, WJG, Blower, PJ, Mather, SJ, Boerman, OC & Sosabowski, JK 2014, 'PET and SPECT imaging of a radiolabeled minigastrin analogue conjugated with DOTA, NOTA, and NODAGA and labeled with ⁶⁴Cu, ⁶⁸Ga, and ¹¹¹In', Molecular Pharmaceutics, vol. 11, no. 11, pp. 3930-3937. https://doi.org/10.1021/mp500283k

TY - JOUR

T1 - PET and SPECT imaging of a radiolabeled minigastrin analogue conjugated with DOTA, NOTA, and NODAGA and labeled with 64Cu, 68Ga, and 111In

AU - Roosenburg, S.

AU - Laverman, P.

AU - Joosten, L.

AU - Cooper, M. S.

AU - Kolenc-Peitl, P. K.

AU - Foster, J. M.

AU - Hudson, C.

AU - Leyton, J.

AU - Burnet, J.

AU - Oyen, W. J.G.

AU - Blower, P. J.

AU - Mather, S. J.

AU - Boerman, O. C.

AU - Sosabowski, J. K.

PY - 2014

Y1 - 2014

N2 - Cholecystokinin-2 (CCK-2) receptors, overexpressed in cancer types such as small cell lung cancers (SCLC) and medullary thyroid carcinomas (MTC), may serve as targets for peptide receptor radionuclide imaging. A variety of CCK and gastrin analogues has been developed, but a major drawback is metabolic instability or high kidney uptake. The minigastrin analogue PP-F11 has previously been shown to be a promising peptide for imaging of CCK-2 receptor positive tumors and was therefore further evaluated. The peptide was conjugated with one of the macrocyclic chelators DOTA, NOTA, or NODAGA. The peptide conjugates were then radiolabeled with either 68Ga, 64Cu, or 111In. All (radio)labeled compounds were evaluated in vitro (IC50) and in vivo (biodistribution and PET/CT and SPECT/CT imaging). IC50 values were in the low nanomolar range for all compounds (0.79-1.51 nM). In the biodistribution studies, 68Ga-and 111In-labeled peptides showed higher tumor-to-background ratios than the 64Cu-labeled compounds. All tested radiolabeled compounds clearly visualized the CCK2 receptor positive tumor in PET or SPECT imaging. The chelator did not seem to affect in vivo behavior of the peptide for 111In-and 68Ga-labeled peptides. In contrast, the biodistribution of the 64Cu-labeled peptides showed high uptake in the liver and in other organs, most likely caused by high blood levels, probably due to dissociation of 64Cu from the chelator and subsequent transchelation to proteins. Based on the present study, 68Ga-DOTA-PP-F11 might be a promising radiopharmaceutical for PET/CT imaging of CCK2 receptor expressing tumors such as MTC and SCLC. Clinical studies are warranted to investigate the potential of this tracer.

AB - Cholecystokinin-2 (CCK-2) receptors, overexpressed in cancer types such as small cell lung cancers (SCLC) and medullary thyroid carcinomas (MTC), may serve as targets for peptide receptor radionuclide imaging. A variety of CCK and gastrin analogues has been developed, but a major drawback is metabolic instability or high kidney uptake. The minigastrin analogue PP-F11 has previously been shown to be a promising peptide for imaging of CCK-2 receptor positive tumors and was therefore further evaluated. The peptide was conjugated with one of the macrocyclic chelators DOTA, NOTA, or NODAGA. The peptide conjugates were then radiolabeled with either 68Ga, 64Cu, or 111In. All (radio)labeled compounds were evaluated in vitro (IC50) and in vivo (biodistribution and PET/CT and SPECT/CT imaging). IC50 values were in the low nanomolar range for all compounds (0.79-1.51 nM). In the biodistribution studies, 68Ga-and 111In-labeled peptides showed higher tumor-to-background ratios than the 64Cu-labeled compounds. All tested radiolabeled compounds clearly visualized the CCK2 receptor positive tumor in PET or SPECT imaging. The chelator did not seem to affect in vivo behavior of the peptide for 111In-and 68Ga-labeled peptides. In contrast, the biodistribution of the 64Cu-labeled peptides showed high uptake in the liver and in other organs, most likely caused by high blood levels, probably due to dissociation of 64Cu from the chelator and subsequent transchelation to proteins. Based on the present study, 68Ga-DOTA-PP-F11 might be a promising radiopharmaceutical for PET/CT imaging of CCK2 receptor expressing tumors such as MTC and SCLC. Clinical studies are warranted to investigate the potential of this tracer.

KW - CCK2R peptide

KW - Cu-64

KW - DOTA

KW - Ga-68

KW - In-111

KW - Macrocyclic chelator

KW - NODAGA

KW - NOTA

KW - PET imaging

UR - http://www.scopus.com/inward/record.url?scp=84933546506&partnerID=8YFLogxK

U2 - 10.1021/mp500283k

DO - 10.1021/mp500283k

M3 - Article

C2 - 24992368

AN - SCOPUS:84933546506

SN - 1543-8384

VL - 11

SP - 3930

EP - 3937

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

IS - 11

ER -