Exploring the radiochemistry of PARP inhibitors: a new era in therapy and imaging

Abstract

Background: Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a promising class of therapeutics, particularly in the treatment of cancers with defective DNA repair mechanisms, such as those with breast cancer genes (BRCA) mutations. Their effectiveness in cancer therapy is now well-established, but the ongoing advancements in radiochemistry are expanding their potential to combine both therapeutic and imaging capabilities. Radiolabelled PARP inhibitors, used in conjunction with positron emission tomography (PET) or single-photon emission computed tomography (SPECT), might enable precise imaging of PARP expression in tumours, potentially providing invaluable insights into treatment response, tumor heterogeneity, and molecular profiling.

Main body: The radiochemistry of PARP inhibitors involves incorporating radioisotopes (most of all Fluorine-18) into the molecular structure of these molecules. The first strategy used to achieve this goal was the use of prosthetic groups bearing the fluorine-18. Then, the development of radioisotopologue have gained ground, followed later by the replacement with other halogens such as bromine, iodine, or astatine has taken place. Another frontier is represented by the metal radiolabelling of these inhibitors through the introduction of a chelator moiety to these molecules, thus further expanding both imaging and therapy applications.

Conclusion: Finally, emerging evidence suggest the possibility to involve PARP-related radiopharmaceuticals in theranostics approaches. Despite challenges such as the complexity of radiolabelling, regulatory hurdles, and the need for more robust clinical validation, the continued exploration of the radiochemistry of PARP inhibitors promises to revolutionize both the diagnosis and treatment of cancer, offering hope for more effective and personalized cancer care.

Keywords: Niraparib; Olaparib; PARP; PARP imaging; PARP inhibitor; PARP therapy; PARP1; Radiolabelling; Rucaparib; Talazoparib.

Fig. 1

Molecular structures of approved PARP inhibitors

Fig. 2

Radiosynthesis of [¹⁸F]BO

Fig. 3

Radiosynthesis of [¹⁸F]PARPi-FL via acid catalysed fluorine-18/fluorine-19 exchange

Fig. 4

Radiosynthesis of [¹⁸F]FTT

Fig. 5

Radiosynthesis of [¹⁸F]PARPi

Fig. 6

Improved radiosynthesis of [¹⁸F]PARPi by Wilson and colleagues

Fig. 7

Radiosynthesis of [¹⁸F]20

Fig. 8

Radiosynthesis of [¹⁸F]WC-DZ-F

Fig. 9

Manual and automated radiosynthesis of [¹⁸F]Olaparib

Fig. 10

Radiosynthesis of [¹⁸F]9e

Fig. 11

Radiosynthesis of [¹⁸F]SuPAR

Fig. 12

Manual and automated radiosynthesis of [¹⁸F]AZD2461

Fig. 13

Radiosynthesis of [¹⁸F]FpyPARP

Fig. 14

Radiosynthesis of [¹⁸F]Rucaparib

Fig. 15

Radiosynthesis of [¹⁸F]Talazoparib proposed by Bowden and colleagues (Maurer group)

Fig. 16

Radiosynthesis of [¹⁸F]Talazoparib proposed by Zhou and coworkers

Fig. 17

Radiosynthesis of [¹⁸F]Pamiparib

Fig. 18

Radiosynthesis of [¹⁸F]5 ([¹⁸F]AZD9574)

Fig. 19

Radiosynthesis of [¹²⁵I]5

Fig. 20

Radiosynthesis of [^131/124I]-I2-PARPi

Fig. 21

Radiosynthesis of [¹³¹I]PARPi

Fig. 22

Radiosynthesis of [¹²⁵I]KX-02-019 and [¹²⁵I]KX1

Fig. 23

Radiosynthesis of [¹²³I]MAPi and [¹²⁵I]-PARPi-01

Fig. 24

Radiosynthesis of [¹²³I]GD1

Fig. 25

Radiosynthesis of [¹²³I]CC1

Fig. 26

Radiosynthesis of [⁷⁷Br]Olaparib derivative

Fig. 27

Radiosynthesis of [⁷⁷Br]KX1

Fig. 28

Radiosynthesis of 20 (Olaparib derivative) and 21 (RD1)

Fig. 29

Radiosynthesis of [⁷⁷Br]Br-WC-DZ

Fig. 30

Radiosynthesis of [²¹¹At]MM4

Fig. 31

Radiosynthesis of [¹¹C]PJ34

Fig. 32

Radiosynthesis of [¹¹C]Olaparib

Fig. 33

Radiosynthesis of [¹¹C]Niraparib and [¹¹C]Veliparib

Fig. 34

Radiosynthesis of [⁶⁴Cu]Olaparib DOTA derivative

Fig. 35

Radiosynthesis of [⁶⁸Ga]Ga-DOTA-GABA-Olaparib

Fig. 36

Radiosynthesis of [⁶⁸Ga]Ga-SMIC-2001

Fig. 37

Radiosynthesis of [⁶⁸Ga]Ga-DOTANPB

Fig. 38

Radiosynthesis of [^99mTc]Tc-CNPN

Fig. 39

Radiosynthesis of [^99mTc]Tc-(TPPTS/tricine)-NPBHYNIC and [^99mTc]Tc-(NIC/tricine)-NPBHYNIC

Fig. 40

A timeline showcasing the evolution of radiochemistry in labelling PARP inhibitors