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Development of new folate-based PET radiotracers: preclinical evaluation of 68Ga-DOTA-folate conjugates

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

A number of 111In- and 99mTc-folate-based tracers have been evaluated as diagnostic agents for imaging folate receptor (FR)-positive tumours. A 68Ga-folate-based radiopharmaceutical would be of great interest, combining the advantages of PET technology and the availability of 68Ga from a generator. The aim of the study was to develop a new 68Ga-folate-based PET radiotracer.

Methods

Two new DOTA-folate conjugates, named P3026 and P1254, were synthesized using the 1,2-diaminoethane and 3-{2-[2-(3-amino-propoxy)-ethoxy]-ethoxy}-propylamine as a spacer, respectively. Both conjugates were labelled with 67/68Ga. Binding affinity, internalization and externalization studies were performed using the FR-positive KB cell line. Biodistribution and PET/CT imaging studies were performed in nude mice, on a folate-deficient diet, bearing KB and HT1080 (FR-negative) tumours, concurrently. The new radiotracers were evaluated comparatively to the reference molecule 111In-DTPA-folate (111In-P3139).

Results

The Kd values of 67/68Ga-P3026 (4.65 ± 0.82 nM) and 67/68Ga-P1254 (4.27 ± 0.42 nM) showed high affinity for the FR. The internalization rate followed the order 67/68Ga-P3026 > 67/68Ga-P1254 > 111In-P3139, while almost double cellular retention was found for 67/68Ga-P3026 and 67/68Ga-P1254, compared to 111In-P3139. The biodistribution data of 67/68Ga-DOTA-folates showed high and receptor-mediated uptake on the FR-positive tumours and kidneys, with no significant differences compared to 111In-P3139. PET/CT images, performed with 68Ga-P3026, showed high uptake in the kidneys and clear visualization of the FR-positive tumours.

Conclusion

The DOTA-folate conjugates can be efficiently labelled with 68Ga in labelling yields and specific activities which allow clinical application. The characteristics of the 67/68Ga-DOTA-folates are comparable to 111In-DTPA-folate, which has already been used in clinical trials, showing that the new conjugates are promising candidates as PET radiotracers for FR-positive tumours.

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Abbreviations

TFA:

Trifluoroacetic acid

DCM:

Dichloromethane

Fmoc:

9-Fluorenylmethoxycarbonyl

tBu:

tert-Butyl

NHS:

N-Hydroxysuccinimide

DCC:

Dicyclohexylcarbodiimine

DMSO:

Dimethyl sulfoxide

EDCI:

1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

HOBt:

Hydroxybenzotriazole

DOTA(tBu)3 :

2-(4,7,10-Tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetic acid

HEPES:

4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

BSA:

Bovine serum albumin

PBS:

Phosphate-buffered saline

FCS:

Fetal calf serum

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Acknowledgements

We thank the staff of the Division of Radiological Chemistry and the Department of Nuclear Medicine, University Hospital Basel, for their assistance. This work was supported by a research grant from Guerbet (Aulnay-sous-Bois, France). C. Medina, I. Raynal and M. Rort are employees of Guerbet. M. Fani, X. Wang, G. Nicolas and H.R. Maecke declare that they have no conflict of interest.

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Correspondence to Helmut R. Maecke.

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Fani, M., Wang, X., Nicolas, G. et al. Development of new folate-based PET radiotracers: preclinical evaluation of 68Ga-DOTA-folate conjugates. Eur J Nucl Med Mol Imaging 38, 108–119 (2011). https://doi.org/10.1007/s00259-010-1597-8

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  • DOI: https://doi.org/10.1007/s00259-010-1597-8

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