[ 18 F]RPS-544: A PET tracer for imaging the chemokine receptor CXCR4

Alejandro Amor-Coarasa, James Kelly, Shashikanth Ponnala, Yogindra Vedvyas, Anastasia Nikolopoulou, Clarence Williams, Moonsoo M. Jin, J. David Warren, John W. Babich

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Introduction: CXCR4 specific [ 18 F]-labeled positron emission tomography (PET) imaging agents are needed which would enable general distribution of the radiotracer for clinical investigation. We sought to synthesize, radiolabel and evaluate [ 18 F]RPS-544, a novel non-peptide CXCR4 antagonist as a CXCR4 specific probe. We compared [ 18 F]RPS-544 with the previously published [ 18 F]-3 ([ 18 F]RPS-510 in this paper) in a bi-lateral tumor model of differential CXCR4 expression for its ability to selectively target CXCR4 expression. Methods: Radiolabeling of [ 18 F]RPS-544 and [ 18 F]RPS-510 was performed by aromatic substitution on a 6-nitropyridyl group using no-carrier-added [ 18 F]fluoride under basic conditions. 18 F incorporation was determined by radioHPLC. Semi-preparative HPLC was used to purify the final product prior to reformulation. Imaging and biodistribution was performed in nude mice with bilateral PC3 (CXCR4+ and WT) xenograft tumors at 1, 2 and 4 h post injection. Results: RPS-544 bound CXCR4 with an IC50 of 4.9 ± 0.3 nM. [ 18 F]RPS-544 showed preferential uptake in CXCR4+ tumors, with a CXCR4/WT ratio of 3.3 ± 1.3 at 1 h p.i. and 2.3 ± 0.5 at 2 h p.i. Maximum uptake in the CXCR4+ tumors was 3.4 ± 1.2%ID/g at 1 h p.i., significantly greater (p = 0.003) than the uptake in the WT tumor. Tumor/blood ratios were 2.5 ± 0.4 and 3.6 ± 0.3 at 1 and 2 h p.i. Tumor/muscle ratios were >4 at all time-points. Tumor/lung ratios were >2 at 1 h and 2 h p.i. Substantial uptake was observed in the liver (15–25%ID/g), kidneys (25–35%ID/g), the small intestine (1–7%ID/g) and the large intestine (1–12%ID/g). Blood concentrations varied over time (0.5–2%ID/g). All other organs showed uptake of <1%ID/g at all time points studied with clearance profiles similar to blood clearance. Conclusions: Here we present, to the best of our knowledge, the first high affinity [18F]-labeled tracer, suitable for in vivo PET imaging of CXCR4. [18F]RPS-544 displayed high affinity for CXCR4 and good tumor uptake with a maximum uptake at 1 h p.i. CXCR4 dependent uptake was demonstrated using bilateral tumors with differential CXCR4 expression as well as pharmacological blockade using the known CXCR4 antagonist, AMD-3100. Tissue contrast as judged by tumor to normal tissue ratios was positive in several key tissues. The structural and pharmacological similarities between [18F]RPS-544 and the approved drug AMD-3465, combined with the ease of synthesis and high molar activity (>185 GBq/μmol) achieved during radiosynthesis could lead to accelerated translation into the clinic.

Original languageEnglish (US)
Pages (from-to)37-44
Number of pages8
JournalNuclear Medicine and Biology
Volume60
DOIs
StatePublished - May 2018
Externally publishedYes

Fingerprint

Chemokine Receptors
Positron-Emission Tomography
Neoplasms
Hospital Distribution Systems
Large Intestine
Fluorides
Heterografts
Nude Mice
Inhibitory Concentration 50
Small Intestine
High Pressure Liquid Chromatography
Kidney
Muscles
Lung
Injections
Liver

Keywords

  • Chemokine
  • CXCR4
  • Imaging
  • PET
  • Prognosis

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Amor-Coarasa, A., Kelly, J., Ponnala, S., Vedvyas, Y., Nikolopoulou, A., Williams, C., ... Babich, J. W. (2018). [ 18 F]RPS-544: A PET tracer for imaging the chemokine receptor CXCR4. Nuclear Medicine and Biology, 60, 37-44. https://doi.org/10.1016/j.nucmedbio.2018.01.004

[ 18 F]RPS-544 : A PET tracer for imaging the chemokine receptor CXCR4. / Amor-Coarasa, Alejandro; Kelly, James; Ponnala, Shashikanth; Vedvyas, Yogindra; Nikolopoulou, Anastasia; Williams, Clarence; Jin, Moonsoo M.; David Warren, J.; Babich, John W.

In: Nuclear Medicine and Biology, Vol. 60, 05.2018, p. 37-44.

Research output: Contribution to journalArticle

Amor-Coarasa, A, Kelly, J, Ponnala, S, Vedvyas, Y, Nikolopoulou, A, Williams, C, Jin, MM, David Warren, J & Babich, JW 2018, '[ 18 F]RPS-544: A PET tracer for imaging the chemokine receptor CXCR4', Nuclear Medicine and Biology, vol. 60, pp. 37-44. https://doi.org/10.1016/j.nucmedbio.2018.01.004
Amor-Coarasa, Alejandro ; Kelly, James ; Ponnala, Shashikanth ; Vedvyas, Yogindra ; Nikolopoulou, Anastasia ; Williams, Clarence ; Jin, Moonsoo M. ; David Warren, J. ; Babich, John W. / [ 18 F]RPS-544 : A PET tracer for imaging the chemokine receptor CXCR4. In: Nuclear Medicine and Biology. 2018 ; Vol. 60. pp. 37-44.
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title = "[ 18 F]RPS-544: A PET tracer for imaging the chemokine receptor CXCR4",
abstract = "Introduction: CXCR4 specific [ 18 F]-labeled positron emission tomography (PET) imaging agents are needed which would enable general distribution of the radiotracer for clinical investigation. We sought to synthesize, radiolabel and evaluate [ 18 F]RPS-544, a novel non-peptide CXCR4 antagonist as a CXCR4 specific probe. We compared [ 18 F]RPS-544 with the previously published [ 18 F]-3 ([ 18 F]RPS-510 in this paper) in a bi-lateral tumor model of differential CXCR4 expression for its ability to selectively target CXCR4 expression. Methods: Radiolabeling of [ 18 F]RPS-544 and [ 18 F]RPS-510 was performed by aromatic substitution on a 6-nitropyridyl group using no-carrier-added [ 18 F]fluoride under basic conditions. 18 F incorporation was determined by radioHPLC. Semi-preparative HPLC was used to purify the final product prior to reformulation. Imaging and biodistribution was performed in nude mice with bilateral PC3 (CXCR4+ and WT) xenograft tumors at 1, 2 and 4 h post injection. Results: RPS-544 bound CXCR4 with an IC50 of 4.9 ± 0.3 nM. [ 18 F]RPS-544 showed preferential uptake in CXCR4+ tumors, with a CXCR4/WT ratio of 3.3 ± 1.3 at 1 h p.i. and 2.3 ± 0.5 at 2 h p.i. Maximum uptake in the CXCR4+ tumors was 3.4 ± 1.2{\%}ID/g at 1 h p.i., significantly greater (p = 0.003) than the uptake in the WT tumor. Tumor/blood ratios were 2.5 ± 0.4 and 3.6 ± 0.3 at 1 and 2 h p.i. Tumor/muscle ratios were >4 at all time-points. Tumor/lung ratios were >2 at 1 h and 2 h p.i. Substantial uptake was observed in the liver (15–25{\%}ID/g), kidneys (25–35{\%}ID/g), the small intestine (1–7{\%}ID/g) and the large intestine (1–12{\%}ID/g). Blood concentrations varied over time (0.5–2{\%}ID/g). All other organs showed uptake of <1{\%}ID/g at all time points studied with clearance profiles similar to blood clearance. Conclusions: Here we present, to the best of our knowledge, the first high affinity [18F]-labeled tracer, suitable for in vivo PET imaging of CXCR4. [18F]RPS-544 displayed high affinity for CXCR4 and good tumor uptake with a maximum uptake at 1 h p.i. CXCR4 dependent uptake was demonstrated using bilateral tumors with differential CXCR4 expression as well as pharmacological blockade using the known CXCR4 antagonist, AMD-3100. Tissue contrast as judged by tumor to normal tissue ratios was positive in several key tissues. The structural and pharmacological similarities between [18F]RPS-544 and the approved drug AMD-3465, combined with the ease of synthesis and high molar activity (>185 GBq/μmol) achieved during radiosynthesis could lead to accelerated translation into the clinic.",
keywords = "Chemokine, CXCR4, Imaging, PET, Prognosis",
author = "Alejandro Amor-Coarasa and James Kelly and Shashikanth Ponnala and Yogindra Vedvyas and Anastasia Nikolopoulou and Clarence Williams and Jin, {Moonsoo M.} and {David Warren}, J. and Babich, {John W.}",
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TY - JOUR

T1 - [ 18 F]RPS-544

T2 - A PET tracer for imaging the chemokine receptor CXCR4

AU - Amor-Coarasa, Alejandro

AU - Kelly, James

AU - Ponnala, Shashikanth

AU - Vedvyas, Yogindra

AU - Nikolopoulou, Anastasia

AU - Williams, Clarence

AU - Jin, Moonsoo M.

AU - David Warren, J.

AU - Babich, John W.

PY - 2018/5

Y1 - 2018/5

N2 - Introduction: CXCR4 specific [ 18 F]-labeled positron emission tomography (PET) imaging agents are needed which would enable general distribution of the radiotracer for clinical investigation. We sought to synthesize, radiolabel and evaluate [ 18 F]RPS-544, a novel non-peptide CXCR4 antagonist as a CXCR4 specific probe. We compared [ 18 F]RPS-544 with the previously published [ 18 F]-3 ([ 18 F]RPS-510 in this paper) in a bi-lateral tumor model of differential CXCR4 expression for its ability to selectively target CXCR4 expression. Methods: Radiolabeling of [ 18 F]RPS-544 and [ 18 F]RPS-510 was performed by aromatic substitution on a 6-nitropyridyl group using no-carrier-added [ 18 F]fluoride under basic conditions. 18 F incorporation was determined by radioHPLC. Semi-preparative HPLC was used to purify the final product prior to reformulation. Imaging and biodistribution was performed in nude mice with bilateral PC3 (CXCR4+ and WT) xenograft tumors at 1, 2 and 4 h post injection. Results: RPS-544 bound CXCR4 with an IC50 of 4.9 ± 0.3 nM. [ 18 F]RPS-544 showed preferential uptake in CXCR4+ tumors, with a CXCR4/WT ratio of 3.3 ± 1.3 at 1 h p.i. and 2.3 ± 0.5 at 2 h p.i. Maximum uptake in the CXCR4+ tumors was 3.4 ± 1.2%ID/g at 1 h p.i., significantly greater (p = 0.003) than the uptake in the WT tumor. Tumor/blood ratios were 2.5 ± 0.4 and 3.6 ± 0.3 at 1 and 2 h p.i. Tumor/muscle ratios were >4 at all time-points. Tumor/lung ratios were >2 at 1 h and 2 h p.i. Substantial uptake was observed in the liver (15–25%ID/g), kidneys (25–35%ID/g), the small intestine (1–7%ID/g) and the large intestine (1–12%ID/g). Blood concentrations varied over time (0.5–2%ID/g). All other organs showed uptake of <1%ID/g at all time points studied with clearance profiles similar to blood clearance. Conclusions: Here we present, to the best of our knowledge, the first high affinity [18F]-labeled tracer, suitable for in vivo PET imaging of CXCR4. [18F]RPS-544 displayed high affinity for CXCR4 and good tumor uptake with a maximum uptake at 1 h p.i. CXCR4 dependent uptake was demonstrated using bilateral tumors with differential CXCR4 expression as well as pharmacological blockade using the known CXCR4 antagonist, AMD-3100. Tissue contrast as judged by tumor to normal tissue ratios was positive in several key tissues. The structural and pharmacological similarities between [18F]RPS-544 and the approved drug AMD-3465, combined with the ease of synthesis and high molar activity (>185 GBq/μmol) achieved during radiosynthesis could lead to accelerated translation into the clinic.

AB - Introduction: CXCR4 specific [ 18 F]-labeled positron emission tomography (PET) imaging agents are needed which would enable general distribution of the radiotracer for clinical investigation. We sought to synthesize, radiolabel and evaluate [ 18 F]RPS-544, a novel non-peptide CXCR4 antagonist as a CXCR4 specific probe. We compared [ 18 F]RPS-544 with the previously published [ 18 F]-3 ([ 18 F]RPS-510 in this paper) in a bi-lateral tumor model of differential CXCR4 expression for its ability to selectively target CXCR4 expression. Methods: Radiolabeling of [ 18 F]RPS-544 and [ 18 F]RPS-510 was performed by aromatic substitution on a 6-nitropyridyl group using no-carrier-added [ 18 F]fluoride under basic conditions. 18 F incorporation was determined by radioHPLC. Semi-preparative HPLC was used to purify the final product prior to reformulation. Imaging and biodistribution was performed in nude mice with bilateral PC3 (CXCR4+ and WT) xenograft tumors at 1, 2 and 4 h post injection. Results: RPS-544 bound CXCR4 with an IC50 of 4.9 ± 0.3 nM. [ 18 F]RPS-544 showed preferential uptake in CXCR4+ tumors, with a CXCR4/WT ratio of 3.3 ± 1.3 at 1 h p.i. and 2.3 ± 0.5 at 2 h p.i. Maximum uptake in the CXCR4+ tumors was 3.4 ± 1.2%ID/g at 1 h p.i., significantly greater (p = 0.003) than the uptake in the WT tumor. Tumor/blood ratios were 2.5 ± 0.4 and 3.6 ± 0.3 at 1 and 2 h p.i. Tumor/muscle ratios were >4 at all time-points. Tumor/lung ratios were >2 at 1 h and 2 h p.i. Substantial uptake was observed in the liver (15–25%ID/g), kidneys (25–35%ID/g), the small intestine (1–7%ID/g) and the large intestine (1–12%ID/g). Blood concentrations varied over time (0.5–2%ID/g). All other organs showed uptake of <1%ID/g at all time points studied with clearance profiles similar to blood clearance. Conclusions: Here we present, to the best of our knowledge, the first high affinity [18F]-labeled tracer, suitable for in vivo PET imaging of CXCR4. [18F]RPS-544 displayed high affinity for CXCR4 and good tumor uptake with a maximum uptake at 1 h p.i. CXCR4 dependent uptake was demonstrated using bilateral tumors with differential CXCR4 expression as well as pharmacological blockade using the known CXCR4 antagonist, AMD-3100. Tissue contrast as judged by tumor to normal tissue ratios was positive in several key tissues. The structural and pharmacological similarities between [18F]RPS-544 and the approved drug AMD-3465, combined with the ease of synthesis and high molar activity (>185 GBq/μmol) achieved during radiosynthesis could lead to accelerated translation into the clinic.

KW - Chemokine

KW - CXCR4

KW - Imaging

KW - PET

KW - Prognosis

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