Recent advances in the development of 225Ac- and 211At-labeled radioligands for radiotheranostics

Abstract

Radiotheranostics utilizes a set of radioligands incorporating diagnostic or therapeutic radionuclides to achieve both diagnosis and therapy. Imaging probes using diagnostic radionuclides have been used for systemic cancer imaging. Integration of therapeutic radionuclides into the imaging probes serves as potent agents for radionuclide therapy. Among them, targeted alpha therapy (TAT) is a promising next-generation cancer therapy. The α-particles emitted by the radioligands used in TAT result in a high linear energy transfer over a short range, inducing substantial damage to nearby cells surrounding the binding site. Therefore, the key to successful cancer treatment with minimal side effects by TAT depends on the selective delivery of radioligands to their targets. Recently, TAT agents targeting biomolecules highly expressed in various cancer cells, such as sodium/iodide symporter, norepinephrine transporter, somatostatin receptor, α_vβ₃ integrin, prostate-specific membrane antigen, fibroblast-activation protein, and human epidermal growth factor receptor 2 have been developed and have made remarkable progress toward clinical application. In this review, we focus on two radionuclides, ²²⁵Ac and ²¹¹At, which are expected to have a wide range of applications in TAT. We also introduce recent fundamental and clinical studies of radiopharmaceuticals labeled with these radionuclides.

Keywords: Cancer; Molecular Imaging; Radiopharmaceuticals; Radiotheranostics; Targeted alpha therapy.

Fig. 1

Decay scheme of ²²⁵Ac

Fig. 2

Decay scheme of ²¹¹At

Fig. 3

Chemical structures of [¹²³I]MIBG (a), [¹³¹I]MIBG (b), and [²¹¹At]MABG (c)

Fig. 4

Chemical structures of [⁶⁸Ga]Ga-DOTATATE (a), [⁶⁸Ga]Ga-DOTATOC (b), DOTATATE derivatives labeled with ¹⁷⁷Lu or ²²⁵Ac (c), DOTATOC derivatives labeled with ¹⁷⁷Lu or ²²⁵Ac (d), and [²²⁵Ac]Ac-MACROPATATE (e)

Fig. 4

Chemical structures of [⁶⁸Ga]Ga-DOTATATE (a), [⁶⁸Ga]Ga-DOTATOC (b), DOTATATE derivatives labeled with ¹⁷⁷Lu or ²²⁵Ac (c), DOTATOC derivatives labeled with ¹⁷⁷Lu or ²²⁵Ac (d), and [²²⁵Ac]Ac-MACROPATATE (e)

Fig. 5

A 54-year-old woman with rectal NET received combination therapy of [¹⁷⁷Lu]Lu-DOTATATE and capecitabine. Initial [⁶⁸Ga]Ga-DOTANOC PET/CT revealed widespread skeletal metastases (a). After two cycles of [²²⁵Ac]Ac-DOTATATE, follow-up scan indicated partial morphological and molecular response. Reproduced with some modifications from Eur J Nucl Med Mol Imaging, 47, 934–946 (2020), with permission [64]

Fig. 6

Structures of [¹⁸⁶Re]Re-MAG3-HBP (a), [⁹⁰Y]Y-DOTA-HBP (b), [¹⁷⁷Lu]Lu-BPAMD (c), [²¹¹At]ABPB (d), and [²¹¹At]APPB (e)

Fig. 7

Structures of [⁶⁸Ga]Ga-DOTA-E[c(RGDfK)]₂ and [¹⁷⁷Lu]Lu-DOTA-E[c(RGDfK)]₂

Fig. 8

The maximum intensity projection (MIP) image of [⁶⁸Ga]Ga-DOTA-E[c(RGDfK)]₂ PET/CT for pretreatment assessment (a) and transaxial fused PET/CT images showed increased tracer uptake in the thyroid remnant [maximum standardized uptake value (SUVmax) = 4.7] with cervical lymph nodes (b), mediastinal lymph node (c; SUVmax = 8.4), lytic skeletal lesions with soft tissue component in the sternum (c; SUVmax = 7.8) and left iliac bone (d; SUVmax = 8.4) and multiple lung nodules (e). The patient received 5.5 GBq of [¹⁷⁷Lu]Lu-DOTA-E[c(RGDfK)]₂ with post-therapy whole-body images in anterior (f) and posterior (g) views revealing the overall distribution of [¹⁷⁷Lu]Lu-DOTA-E[c(RGDfK)]₂ ¹⁷⁷Lu-DOTA-RGD₂ and transaxial fused SPECT/CT images (h–k) showing tracer uptake at sites corresponding to [⁶⁸Ga]Ga-DOTA-E[c(RGDfK)]₂-avid lesions. Post-therapy follow-up [⁶⁸Ga]Ga-DOTA-E[c(RGDfK)]₂ PET/CT MIP image (l) and transaxial fused PET/CT images showed tracer uptake in the thyroid remnant (SUVmax = 3.0 vs 4.7) with cervical lymph nodes (m), mediastinal lymph node (n; SUVmax = 7.7 vs 8.4), lytic skeletal lesions with significant reduction in soft tissue component in the sternum (n; SUVmax = 6.6 vs 7.8) and left iliac bone (o; SUVmax 8.1 vs 8.4) and multiple lung nodules (p), suggesting response to therapy. This research was originally published in EJNMMI [90]

Fig. 9

Structures of [²¹¹At]c[RGDf(4-At)K] (a), [¹²⁵I]c[RGDf(4-I)K] (b), [⁶⁷Ga]Ga-DOTA-c[RGDf(4-I)K] (c), Ga-DOTA-[²¹¹At]c[RGDf(4-At)K] (d), and Ga-DOTA-K([²¹¹At]APBA)-c(RGDfK) (e)

Fig. 10

Structures of [⁶⁸Ga]Ga-PSMA-11 (a), [¹⁷⁷Lu]Lu-PSMA-617 (b), [²²⁵Ac]Ac-PNT-DA1 (c), and [²²⁵Ac]Ac-L1 (d)

Fig. 11

[⁶⁸Ga]Ga-PSMA-11 PET/CT scans of a patient. Pretherapeutic tumor spread (a), restaging 2 months after third cycle of [²²⁵Ac]Ac-PSMA-617 (b), and restaging 2 months after one additional consolidation therapy (c). This research was originally published in JNM [103]

Fig. 12

Structures of (2S)-2-(3-(1-carboxy-5-(4-²¹¹At-astatobenzamido)pentyl)ureido)-pentanedioic acid (a), ²¹¹At-3-Lu (b), [¹⁸F]F-PSMA-1007 (Pylarify®) (c), [²¹¹At]At-PSMA1 (d), [²¹¹At]At-PSMA5 (e), and [²¹¹At]At-PSMA6 (f)

Fig. 12

Structures of (2S)-2-(3-(1-carboxy-5-(4-²¹¹At-astatobenzamido)pentyl)ureido)-pentanedioic acid (a), ²¹¹At-3-Lu (b), [¹⁸F]F-PSMA-1007 (Pylarify®) (c), [²¹¹At]At-PSMA1 (d), [²¹¹At]At-PSMA5 (e), and [²¹¹At]At-PSMA6 (f)

Fig. 13

Structures of [²²⁵Ac]Ac-FAPI-04 (a) and [²²⁵Ac]Ac-FAPI-46 (b)

Fig. 14

Structures of [²¹¹At]At-FAPI-04 (a), [²¹¹At]At-FAPI1 (b), [²¹¹At]At-FAPI2 (c), [²¹¹At]At-FAPI3 (d), [²¹¹At]At-FAPI4 (e), and [²¹¹At]At-FAPI5 (f)

Fig. 15

Structures and properties of immunoglobulin G (IgG) antibodies and variable fragments of heavy chain antibodies (VHH). CH constant heavy; VH variable heavy; VL variable light

Fig. 16

Structures of 4-(4-iodophenyl)butyric acid (a), and Evans blue (b)

Fig. 17

Structures of SibuDAB (a), mcp-M-alb-PSMA (b), and mcp-d-alb-PSMA (c)