PET and SPECT Tracer Development via Copper-Mediated Radiohalogenation of Divergent and Stable Aryl-Boronic Esters

Abstract

Background/Objectives: Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are highly sensitive clinical imaging modalities, frequently employed in conjunction with magnetic resonance imaging (MRI) or computed tomography (CT) for diagnosing a wide range of disorders. Efficient and robust radiolabeling methods are needed to accommodate the increasing demand for PET and SPECT tracer development. Copper-mediated radiohalogenation (CMRH) reactions enable rapid late-stage preparation of radiolabeled arenes, yet synthetic challenges and radiolabeling precursors' instability can limit the applications of CMRH approaches. Methods: A series of aryl-boronic acids were converted into their corresponding aryl-boronic acid 1,1,2,2-tetraethylethylene glycol esters [ArB(Epin)s] and aryl-boronic acid 1,1,2,2-tetrapropylethylene glycol esters [ArB(Ppin)s] as stable and versatile precursor building blocks for radiolabeling via CMRH. General protocols for the preparation of ¹⁸F-labeled and ¹²³I-labeled arenes utilizing CMRH of these substrates were developed and applied. The radiochemical conversions (RCC) were determined by radio-(U)HPLC. Results: Both ArB(Epin)s and ArB(Ppin)s-based radiolabeling precursors were prepared in a one-step synthesis with chemical yields of 49-99%. Radiolabeling of the aryl-boronic esters with fluorine-18 or iodine-123 via CMRH furnished the corresponding radiolabeled arenes with RCC of 7-99% and 10-99%, respectively. Notably, a radiohalogenated prosthetic group containing a vinyl sulfone motif was obtained with an activity yield (AY) of 18 ± 3%, and applied towards the preparation of two clinically relevant PET tracers. Conclusions: This approach enables the synthesis of stable radiolabeling precursors and thus provides increased versatility in the application of CMRH, thereby supporting the development of novel PET and SPECT radiotracers.

Keywords: 123I-iodination; 18F-fluorination; copper-mediated radiohalogenation (CMRH); positron emission tomography (PET); prosthetic group; radiohalogenation; single-photon emission computed tomography (SPECT).

Scheme 1

(A–D) Previous CMRH preparations of radiolabeled arenes. (E) This work: Preparation of radiolabeled arenes via CMRH of divergent ArB(Epin/Ppin) substrates.

Scheme 2

Preparation of (A) Epin (2) and (B) Ppin (4) from commercially available reagents.

Scheme 3

Preparation of ArB(Epin) and ArB(Ppin) radiolabeling precursors (5a–23a) and (5b–23b), respectively, from aryl-boronic acids. Conditions: ArB(OH)₂ 1 (1.0 equiv), Epin (1.2 equiv), and Na₂SO₄ (2.0 equiv.) in CH₂Cl₂ (0.50 M) at 40 °C for 16 h.

Scheme 4

Preparation of divergent radiolabeling precursor 36 and reference compounds 33 and 35.

Figure 1

(A) UV-visualized TLC experiment using radiolabeling precursors 37, 38, 5a, and 5b, mobile phase: cyclohexane/EtOAc (4:1); (B) Stability studies using aliquots of 38, 5a, and 5b in MeCN/H₂O (1:1).

Figure 2

(A) ¹⁸F-Fluorination optimization with varying Cu mediator equivalents; and (B) CMRF optimization with various reaction solvents.

Scheme 5

Substrate scope for the CMRI of ArB(Epin)s and ArB(Ppin)s. Radiolabeled products were prepared from the respective [a] (hetero)ArB(Epin), or [b] (hetero)ArB(Ppin) precursors. If not otherwise stated, mean (±) standard deviation values for RCC are provided. All experiments were performed at least in duplicate.

Scheme 6

Substrate scope for the CMRF of ArB(Epin)s and ArB(Ppin)s. Radiolabeled products were prepared from the respective [a] (hetero)ArB(Epin), or [b] (hetero)ArB(Ppin) precursors. If not otherwise stated, mean (±) standard deviation values for RCC are provided. All experiments were performed at least in triplicate.

Scheme 7

(A) Preparation of [¹⁸F]33; (B–D) Regioselective ¹⁸F-fluorination compounds via cysteine bioconjugation using [¹⁸F]33. Reaction conditions: Cys-containing compound (0.5–3.0 mg), [¹⁸F]33 (50–500 MBq), sodium borate buffer pH 8.5/MeOH (1:1, 1–2 mL), 35 °C, 30 min. Radio-HPLC was used to determine the non-isolated RCC values of the radiolabeled products. The RCC was calculated by the division of the integrated product peak area by the total integrated ¹⁸F-labeled peaks. The identity of the ¹⁸F-labeled products was confirmed by coinjection with the “cold” ¹⁹F-reference standard.