Comparing Two Folate Receptor β-Targeted Tracers in a Rat Model of Experimental Autoimmune Myocarditis

Erika Atencio Herre; Xiang-Guo Li; Heidi Liljenback; Senthil Palani; Putri Andriana; Arghavan Jahandideh; Jenni Virta; Imran Iqbal; Pyry Dillemuth; Jonne Kunnas; Maxwell W. G. Miner; Johan Rajander; Hasan Mansour; Nathan A. Cleveland; Madduri Srinivasarao; Philip S. Low; Juhani Knuuti; Antti Saraste; Anne Roivainen

doi:10.1021/acsptsci.4c00749

Comparing Two Folate Receptor β-Targeted Tracers in a Rat Model of Experimental Autoimmune Myocarditis

Erika Atencio Herre
, Xiang-Guo Li
, Heidi Liljenback
, Senthil Palani
, Putri Andriana
, Arghavan Jahandideh
, Jenni Virta
, Imran Iqbal
, Pyry Dillemuth
, Jonne Kunnas
, Maxwell W. G. Miner
, Johan Rajander
, Hasan Mansour
, Nathan A. Cleveland
, Madduri Srinivasarao
, Philip S. Low
, Juhani Knuuti
, Antti Saraste
, Anne Roivainen

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

Abstract

Folate receptor β (FR-β) expression may serve as a marker of activated macrophages involved in autoimmune myocarditis. The positron emission tomography (PET) tracer N-succinimidyl 4-[ ¹⁸F]fluorobenzoate-conjugated folate ([ ¹⁸F]SFB-FOL) effectively targets FR-β-positive macrophages in rheumatoid arthritis. Here, we examined [ ¹⁸F]SFB-FOL for detecting myocardial inflammation via FR-β in a rat model of experimental autoimmune myocarditis (EAM), in comparison with the established FR-β-targeted PET tracer aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate ([ ¹⁸F]FOL). EAM was induced in 22 Lewis rats through cardiac myosin immunization. Rats underwent 2-deoxy-2-[ ¹⁸F]fluoro-d-glucose ([ ¹⁸F]FDG) PET to visualize myocardium, followed by dynamic PET with [ ¹⁸F]SFB-FOL or [ ¹⁸F]FOL at Days 14, 21, or 28 postimmunization. Postimaging, myocardial tissues were assessed by γ-counting, autoradiography, and CD68 immunohistochemistry to quantify macrophage presence. Both tracers showed high radiochemical purity and in vivo stability. Inflammation-rich myocardial lesions were confirmed, with macrophages occupying 9.9% ± 1.1 of the tissue area. PET imaging revealed significantly higher uptake of both tracers in inflamed myocardium versus remote areas, confirmed by histology and autoradiography. Lesion-to-remote uptake ratios were 5.7 ± 1.8 for [ ¹⁸F]SFB-FOL and 3.8 ± 0.5 for [ ¹⁸F]FOL. Blood clearance and renal excretion were rapid for both tracers. No significant differences were observed in tracer uptake or macrophage density between Days 21 and 28. [ ¹⁸F]SFB-FOL is a suitable tracer for detecting active myocardial inflammation via FR-β in EAM and performs comparably to [ ¹⁸F]FOL.

Original language	English
Pages (from-to)	3453-3462
Number of pages	10
Journal	ACS Pharmacology and Translational Science
Volume	8
Issue number	10
DOIs	https://doi.org/10.1021/acsptsci.4c00749
Publication status	Published - 10 Oct 2025
MoE publication type	A1 Journal article-refereed

Funding

The study was supported financially by grants from the Jane and Aatos Erkko Foundation, the Sigrid Jusélius Foundation, the Finnish Foundation for Cardiovascular Research, the Research Council of Finland (#350117, #343152), and the Turku University Foundation. E.A.H. is a PhD student supported in part by the Drug Research Doctoral Programme of the University of Turku Graduate School and by the doctoral module of the InFLAMES Flagship.

Keywords

Pet
Experimental autoimmune myocarditis
Folate
Folate receptor beta
Myocarditis

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10.1021/acsptsci.4c00749Licence: CC BY

comparing-two-folate-receptor-β-targeted-tracers-in-a-rat-model-of-experimental-autoimmune-myocarditisFinal published version, 7.96 MBLicence: CC BY

https://urn.fi/URN:NBN:fi-fe20251205114785

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Herre, E. A., Li, X.-G., Liljenback, H., Palani, S., Andriana, P., Jahandideh, A., Virta, J., Iqbal, I., Dillemuth, P., Kunnas, J., Miner, M. W. G., Rajander, J., Mansour, H., Cleveland, N. A., Srinivasarao, M., Low, P. S., Knuuti, J., Saraste, A., & Roivainen, A. (2025). Comparing Two Folate Receptor β-Targeted Tracers in a Rat Model of Experimental Autoimmune Myocarditis. ACS Pharmacology and Translational Science, 8(10), 3453-3462. https://doi.org/10.1021/acsptsci.4c00749

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title = "Comparing Two Folate Receptor β-Targeted Tracers in a Rat Model of Experimental Autoimmune Myocarditis",

abstract = "Folate receptor β (FR-β) expression may serve as a marker of activated macrophages involved in autoimmune myocarditis. The positron emission tomography (PET) tracer N-succinimidyl 4-[ 18F]fluorobenzoate-conjugated folate ([ 18F]SFB-FOL) effectively targets FR-β-positive macrophages in rheumatoid arthritis. Here, we examined [ 18F]SFB-FOL for detecting myocardial inflammation via FR-β in a rat model of experimental autoimmune myocarditis (EAM), in comparison with the established FR-β-targeted PET tracer aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate ([ 18F]FOL). EAM was induced in 22 Lewis rats through cardiac myosin immunization. Rats underwent 2-deoxy-2-[ 18F]fluoro-d-glucose ([ 18F]FDG) PET to visualize myocardium, followed by dynamic PET with [ 18F]SFB-FOL or [ 18F]FOL at Days 14, 21, or 28 postimmunization. Postimaging, myocardial tissues were assessed by γ-counting, autoradiography, and CD68 immunohistochemistry to quantify macrophage presence. Both tracers showed high radiochemical purity and in vivo stability. Inflammation-rich myocardial lesions were confirmed, with macrophages occupying 9.9\% ± 1.1 of the tissue area. PET imaging revealed significantly higher uptake of both tracers in inflamed myocardium versus remote areas, confirmed by histology and autoradiography. Lesion-to-remote uptake ratios were 5.7 ± 1.8 for [ 18F]SFB-FOL and 3.8 ± 0.5 for [ 18F]FOL. Blood clearance and renal excretion were rapid for both tracers. No significant differences were observed in tracer uptake or macrophage density between Days 21 and 28. [ 18F]SFB-FOL is a suitable tracer for detecting active myocardial inflammation via FR-β in EAM and performs comparably to [ 18F]FOL.",

keywords = "Pet, Experimental autoimmune myocarditis, Folate, Folate receptor beta, Myocarditis",

author = "Herre, \{Erika Atencio\} and Xiang-Guo Li and Heidi Liljenback and Senthil Palani and Putri Andriana and Arghavan Jahandideh and Jenni Virta and Imran Iqbal and Pyry Dillemuth and Jonne Kunnas and Miner, \{Maxwell W. G.\} and Johan Rajander and Hasan Mansour and Cleveland, \{Nathan A.\} and Madduri Srinivasarao and Low, \{Philip S.\} and Juhani Knuuti and Antti Saraste and Anne Roivainen",

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month = oct,

day = "10",

doi = "10.1021/acsptsci.4c00749",

language = "English",

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Herre, EA, Li, X-G, Liljenback, H, Palani, S, Andriana, P, Jahandideh, A, Virta, J, Iqbal, I, Dillemuth, P, Kunnas, J, Miner, MWG, Rajander, J, Mansour, H, Cleveland, NA, Srinivasarao, M, Low, PS, Knuuti, J, Saraste, A & Roivainen, A 2025, 'Comparing Two Folate Receptor β-Targeted Tracers in a Rat Model of Experimental Autoimmune Myocarditis', ACS Pharmacology and Translational Science, vol. 8, no. 10, pp. 3453-3462. https://doi.org/10.1021/acsptsci.4c00749

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T1 - Comparing Two Folate Receptor β-Targeted Tracers in a Rat Model of Experimental Autoimmune Myocarditis

AU - Herre, Erika Atencio

AU - Li, Xiang-Guo

AU - Liljenback, Heidi

AU - Palani, Senthil

AU - Andriana, Putri

AU - Jahandideh, Arghavan

AU - Virta, Jenni

AU - Iqbal, Imran

AU - Dillemuth, Pyry

AU - Kunnas, Jonne

AU - Miner, Maxwell W. G.

AU - Rajander, Johan

AU - Mansour, Hasan

AU - Cleveland, Nathan A.

AU - Srinivasarao, Madduri

AU - Low, Philip S.

AU - Knuuti, Juhani

AU - Saraste, Antti

AU - Roivainen, Anne

PY - 2025/10/10

Y1 - 2025/10/10

N2 - Folate receptor β (FR-β) expression may serve as a marker of activated macrophages involved in autoimmune myocarditis. The positron emission tomography (PET) tracer N-succinimidyl 4-[ 18F]fluorobenzoate-conjugated folate ([ 18F]SFB-FOL) effectively targets FR-β-positive macrophages in rheumatoid arthritis. Here, we examined [ 18F]SFB-FOL for detecting myocardial inflammation via FR-β in a rat model of experimental autoimmune myocarditis (EAM), in comparison with the established FR-β-targeted PET tracer aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate ([ 18F]FOL). EAM was induced in 22 Lewis rats through cardiac myosin immunization. Rats underwent 2-deoxy-2-[ 18F]fluoro-d-glucose ([ 18F]FDG) PET to visualize myocardium, followed by dynamic PET with [ 18F]SFB-FOL or [ 18F]FOL at Days 14, 21, or 28 postimmunization. Postimaging, myocardial tissues were assessed by γ-counting, autoradiography, and CD68 immunohistochemistry to quantify macrophage presence. Both tracers showed high radiochemical purity and in vivo stability. Inflammation-rich myocardial lesions were confirmed, with macrophages occupying 9.9% ± 1.1 of the tissue area. PET imaging revealed significantly higher uptake of both tracers in inflamed myocardium versus remote areas, confirmed by histology and autoradiography. Lesion-to-remote uptake ratios were 5.7 ± 1.8 for [ 18F]SFB-FOL and 3.8 ± 0.5 for [ 18F]FOL. Blood clearance and renal excretion were rapid for both tracers. No significant differences were observed in tracer uptake or macrophage density between Days 21 and 28. [ 18F]SFB-FOL is a suitable tracer for detecting active myocardial inflammation via FR-β in EAM and performs comparably to [ 18F]FOL.

AB - Folate receptor β (FR-β) expression may serve as a marker of activated macrophages involved in autoimmune myocarditis. The positron emission tomography (PET) tracer N-succinimidyl 4-[ 18F]fluorobenzoate-conjugated folate ([ 18F]SFB-FOL) effectively targets FR-β-positive macrophages in rheumatoid arthritis. Here, we examined [ 18F]SFB-FOL for detecting myocardial inflammation via FR-β in a rat model of experimental autoimmune myocarditis (EAM), in comparison with the established FR-β-targeted PET tracer aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated folate ([ 18F]FOL). EAM was induced in 22 Lewis rats through cardiac myosin immunization. Rats underwent 2-deoxy-2-[ 18F]fluoro-d-glucose ([ 18F]FDG) PET to visualize myocardium, followed by dynamic PET with [ 18F]SFB-FOL or [ 18F]FOL at Days 14, 21, or 28 postimmunization. Postimaging, myocardial tissues were assessed by γ-counting, autoradiography, and CD68 immunohistochemistry to quantify macrophage presence. Both tracers showed high radiochemical purity and in vivo stability. Inflammation-rich myocardial lesions were confirmed, with macrophages occupying 9.9% ± 1.1 of the tissue area. PET imaging revealed significantly higher uptake of both tracers in inflamed myocardium versus remote areas, confirmed by histology and autoradiography. Lesion-to-remote uptake ratios were 5.7 ± 1.8 for [ 18F]SFB-FOL and 3.8 ± 0.5 for [ 18F]FOL. Blood clearance and renal excretion were rapid for both tracers. No significant differences were observed in tracer uptake or macrophage density between Days 21 and 28. [ 18F]SFB-FOL is a suitable tracer for detecting active myocardial inflammation via FR-β in EAM and performs comparably to [ 18F]FOL.

KW - Pet

KW - Experimental autoimmune myocarditis

KW - Folate

KW - Folate receptor beta

KW - Myocarditis

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Comparing Two Folate Receptor β-Targeted Tracers in a Rat Model of Experimental Autoimmune Myocarditis

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