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. 2011 Jan;38(1):128-37.
doi: 10.1007/s00259-010-1615-x. Epub 2010 Sep 21.

PET imaging of αvβ₃ integrin expression in tumours with ⁶⁸Ga-labelled mono-, di- and tetrameric RGD peptides

Ingrid Dijkgraaf  1 , Cheng-Bin Yim, Gerben M Franssen, Robert C Schuit, Gert Luurtsema, Shuang Liu, Wim J G Oyen, Otto C Boerman
Affiliations

PET imaging of αvβ₃ integrin expression in tumours with ⁶⁸Ga-labelled mono-, di- and tetrameric RGD peptides

Ingrid Dijkgraaf et al. Eur J Nucl Med Mol Imaging. 2011 Jan.

Abstract

Purpose: Due to the restricted expression of α(v)β(3) in tumours, α(v)β(3) is considered a suitable receptor for tumour targeting. In this study the α(v)β(3)-binding characteristics of (68)Ga-labelled monomeric, dimeric and tetrameric RGD peptides were determined and compared with their (111)In-labelled counterparts.

Methods: A monomeric (E-c(RGDfK)), a dimeric (E-[c(RGDfK)](2)) and a tetrameric (E{E[c(RGDfK)](2)}(2)) RGD peptide were synthesised, conjugated with DOTA and radiolabelled with (68)Ga. In vitro α(v)β(3)-binding characteristics were determined in a competitive binding assay. In vivo α(v)β(3)-targeting characteristics of the compounds were assessed in mice with subcutaneously growing SK-RC-52 xenografts. In addition, microPET images were acquired using a microPET/CT scanner.

Results: The IC(50) values for the Ga(III)-labelled DOTA-E-c(RGDfK), DOTA-E-[c(RGDfK)](2) and DOTA-E{E[c(RGDfK)](2)}(2) were 23.9 ± 1.22, 8.99 ± 1.20 and 1.74 ± 1.18 nM, respectively, and were similar to those of the In(III)-labelled mono-, di- and tetrameric RGD peptides (26.6 ± 1.15, 3.34 ± 1.16 and 1.80 ± 1.37 nM, respectively). At 2 h post-injection, tumour uptake of the (68)Ga-labelled mono-, di- and tetrameric RGD peptides (3.30 ± 0.30, 5.24 ± 0.27 and 7.11 ± 0.67%ID/g, respectively) was comparable to that of their (111)In-labelled counterparts (2.70 ± 0.29, 5.61 ± 0.85 and 7.32 ± 2.45%ID/g, respectively). PET scans were in line with the biodistribution data. On all PET scans, the tumour could be clearly visualised.

Conclusion: The integrin affinity and the tumour uptake followed the order of DOTA-tetramer > DOTA-dimer > DOTA-monomer. The (68)Ga-labelled tetrameric RGD peptide has excellent characteristics for imaging of α(v)β(3) expression with PET.

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Figures

Fig. 1
Fig. 1
a Structural formula of the DOTA-conjugated monomeric RGD peptide, DOTA-E-c(RGDfK). b Structural formula of the DOTA-conjugated dimeric RGD peptide, DOTA-E-[c(RGDfK)]2. c Structural formula of the DOTA-conjugated tetrameric RGD peptide DOTA-E{E[c(RGDfK)]2}2
Fig. 2
Fig. 2
Competition of specific binding of 111In-DOTA-E-[c(RGDfK)]2 with Ga(III)-DOTA-E-c(RGDfK), Ga(III)-DOTA-E-[c(RGDfK)]2 and Ga(III)-DOTA-E{E[c(RGDfK)]2}2
Fig. 3
Fig. 3
a Biodistribution of [68Ga]DOTA-E-c(RGDfK), [68Ga]DOTA-E-[c(RGDfK)]2 and [68Ga]DOTA-E{E[c(RGDfK)]2}2 at 2 h p.i. in athymic mice with s.c. SK-RC-52 tumours in the absence (five mice/group) or presence (three mice/group) of an excess of DOTA-E-[c(RGDfK)]2. b Biodistribution of [111In]DOTA-E-c(RGDfK), [111In]DOTA-E-[c(RGDfK)]2 and [111In]DOTA-E{E[c(RGDfK)]2}2 at 2 h p.i. in athymic mice with s.c. SK-RC-52 tumours in the absence (five mice/group) or presence (three mice/group) of an excess of DOTA-E-[c(RGDfK)]2
Fig. 4
Fig. 4
Anterior 3-D volume rendering projections of fused PET and CT scans of mice with a s.c. growing SK-RC-52 tumour after i.v. injection of [68Ga]DOTA-E-c(RGDfK) (a), [68Ga]DOTA-E-[c(RGDfK)]2 (b) or [68Ga]DOTA-E{E[c(RGDfK)]2}2 (c). Scans were recorded at 2 h p.i.
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