Folate-based radiotracers for PET imaging--update and perspectives

Abstract

The folate receptor (FR) is expressed in many tumor types, among those ovarian and lung cancer. Due to the high FR affinity of folic acid, it has been used for targeting of FR-positive tumors, allowing specific delivery of attached probes to the malignant tissue. Therefore, nuclear imaging of FR-positive cancer is of clinical interest for selecting patients who could benefit from innovative therapy concepts based on FR-targeting. Positron emission computed tomography (PET) has become an established technique in clinical routine because it provides an increased spatial resolution and higher sensitivity compared to single photon emission computed tomography (SPECT). Therefore, it is of critical importance to develop folate radiotracers suitable for PET imaging. This review article updates on the design, preparation and pre-clinical investigation of folate derivatives for radiolabeling with radioisotopes for PET. Among those the most relevant radionuclides so far are fluorine-18 (t(1/2): 110 min, E(av) β⁺: 250 keV) and gallium-68 (t(1/2): 68 min, E(av) β⁺: 830 keV). Recent results obtained with new PET isotopes such as terbium-152 (t(1/2): 17.5 h, Eβ⁺: 470 keV) or scandium-44 (t(1/2): 3.97 h, (Eav) β⁺: 632 keV) are also presented and discussed. Current endeavors for clinical implementation of PET agents open new perspectives for identification of FR-positive malignancies in patients.

Figure 1

“Folate-Tree”—evolution of folate-based PET agents for ¹⁸F-labeling (yellow) and for radiometallation using variable chelators (pink: DF = deferoxamine; green: NODAGA = 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid; blue: DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) suitable for radiolabeling with ^66/68Ga, ⁴⁴Sc or ¹⁵²Tb.

Figure 2

(A) Chemical structures of [¹⁸F]FBA-γ-folate [63], (B) [¹⁸F]fluoro-benzene-carbohydrazide-folates, (C) [¹⁸F]fluoro-pyridine-carbohydrazide-folate [63], (D) [¹⁸F]fluoro-pyridine-carbohydrazide-methotrexate [67] and (E) [¹⁸F]fluoro-pyridine-carbohydrazide-methotrexate [67].

Figure 3

Radiosynthesis of [¹⁸F]fluoro-click-folate [43] using an azide functionalized folate precursor and 6-[¹⁸F]fluoro-1-hexyne as a prosthetic group. (DIPEA = N,N-diisopropylethylamine).

Figure 4

(A) Chemical structures of [¹⁸F]FDG-folate [74], (B) [¹⁸F]FDG-methotrexate [74] and (C) [¹⁸F]fluoro-deoxy-glucose-folate [45].

Figure 5

PET/CT image of a mouse 75 min after injection of [¹⁸F]fluoro-deoxy-glucose-folate (~14 MBq) [45]. (Tu = KB tumor xenograft, GB = gall bladder, Li = liver, Ki = kidney, Bl = urinary bladder). Reprinted (adapted) with permission from Fischer et al. [45] Copyright (2012) American Chemical Society.

Figure 6

(A) Chemical structures of 2'-[¹⁸F]fluorofolic acid, (B) 3'-aza-2'-[¹⁸F]fluorofolic acid and (C) pemetrexed.

Figure 7

(a) PET/CT image of a tumor bearing mouse 2 h after injection of 3'-aza-2'-[¹⁸F]fluorofolic acid (~29 MBq) [46]. Reprinted (adapted) with permission from Betzel et al. [46] Copyright (2013) American Chemical Society.

Figure 8

(A) Chemical structures of the DOTA-folate P3026 [50], (B) the DOTA-folate P1254 which comprises a short PEG spacer [50], (C) EC0800 (Endocyte Inc., West Lafayette, IN, USA) [85] and (D) DO3A-pteroate [86].

Figure 9

PET/CT images of KB tumor bearing mice. (A) Mouse injected with ⁶⁸Ga-EC0800 (~25 MBq) 1.5 h before scanning and (B) mouse which received pemetrexed (0.4 mg) prior to ⁶⁸Ga-EC0800 (~18 MBq). (Tu = KB tumor xenograft, Ki = kidney, Bl = urinary bladder). Reprinted (adapted) with permission from Müller et al. [6]. Copyright (2013) Bentham Science Publishers.

Figure 10

(A) Chemical structure of the NODAGA-folate P3246 [51] and (B) the NODAGA-dideaza-folate P3238 [51].

Figure 11

MIP PET images of ⁶⁸Ga-P3246 1 h p.i. without (A) and with pre-injection of pemetrexed (B). (Tu = KB tumor xenograft, Ki = kidney) [51]. Reprinted (adapted) with permission from Fani et al. [51]. Copyright (2012) American Chemical Society.

Figure 12

Chemical structure of cm09 composed of three functionalities: folic acid acts as a targeting agent for FR-specific uptake in the tumor tissue; a DOTA-chelator is needed for stable coordination of trivalent radiometals (e.g., ¹⁵²Tb, ⁴⁴Sc); a small molecular weight albumin binding entity is responsible for an enhanced circulation time of the radioconjugate in the blood.

Figure 13

(A) Post mortem PET/CT image of a KB tumor bearing mouse 24 h after injection of ¹⁵²Tb-cm09 (~10 MBq). (B) In vivo PET/CT image of a KB tumor bearing mouse 4 h after injection of ¹⁴⁴Sc-cm09 (~20 MBq).