A Convenient Route to New (Radio)Fluorinated and (Radio)Iodinated Cyclic Tyrosine Analogs

Abstract

The use of radiolabeled non-natural amino acids can provide high contrast SPECT/PET metabolic imaging of solid tumors. Among them, radiohalogenated tyrosine analogs (i.e., [¹²³I]IMT, [¹⁸F]FET, [¹⁸F]FDOPA, [¹²³I]8-iodo-L-TIC(OH), etc.) are of particular interest. While radioiodinated derivatives, such as [¹²³I]IMT, are easily available via electrophilic aromatic substitutions, the production of radiofluorinated aryl tyrosine analogs was a long-standing challenge for radiochemists before the development of innovative radiofluorination processes using arylboronate, arylstannane or iodoniums salts as precursors. Surprisingly, despite these methodological advances, no radiofluorinated analogs have been reported for [¹²³I]8-iodo-L-TIC(OH), a very promising radiotracer for SPECT imaging of prostatic tumors. This work describes a convenient synthetic pathway to obtain new radioiodinated and radiofluorinated derivatives of TIC(OH), as well as their non-radiolabeled counterparts. Using organotin compounds as key intermediates, [¹²⁵I]5-iodo-L-TIC(OH), [¹²⁵I]6-iodo-L-TIC(OH) and [¹²⁵I]8-iodo-L-TIC(OH) were efficiently prepared with good radiochemical yield (RCY, 51-78%), high radiochemical purity (RCP, >98%), molar activity (Am, >1.5-2.9 GBq/µmol) and enantiomeric excess (e.e. >99%). The corresponding [¹⁸F]fluoro-L-TIC(OH) derivatives were also successfully obtained by radiofluorination of the organotin precursors in the presence of tetrakis(pyridine)copper(II) triflate and nucleophilic [¹⁸F]F^- with 19-28% RCY d.c., high RCP (>98.9%), Am (20-107 GBq/µmol) and e.e. (>99%).

Keywords: PET/SPECT imaging; TIC(OH); radiofluorination; radioiodination; tyrosine analogs.

Figure 1

Examples of radioiodinated or radiofluorinated tyrosine analogs.

Figure 2

Examples of TIC(OH)-containing compounds used in medicinal chemistry.

Scheme 1

Retrosynthetic pathway to produce [¹⁹/¹⁸F]fluoro-D/L-TIC(OH) and [¹²⁵I]iodo-L-TIC(OH) from common key organotin intermediates.

Scheme 2

Preparation of iodinated compounds (R/S)-14 (5-iodo-D/L-TIC(OH)) and their ester analogs (R/S)-13. Reagents and conditions: (a) (i) HBr conc., 40 °C, 10 min, (ii) aq. formaldehyde (37–41%), 75 °C, 4 h; (b) (i) NaNO₃, H₂SO₄ conc., 0 °C, 5 min, (ii) NH₄OH conc., pH = 8; (c) SOCl₂, EtOH, reflux, 20 h; (d) NIS, TfOH, r.t., 7.5 h; (e) AcCl, Et₃N, CHCl₃, r.t., 4.5 h; (f) SnCl₂, EtOH, reflux, 1 h; (g) (i) aq. H₂SO₄ 0.5 M, H₂O, 100 °C, 10 min, (ii) NaNO₂, 0 °C, 30 min, (iii) urea, reflux, 30 min; (h) (i) HCl conc., reflux, 7 h, (ii) HCl conc., EtOH, 15 h, (iii) NaHCO₃ sat., pH = 8; (i) (i) HCl 6M, reflux, 4–4.5 h, (ii) aq. KHCO₃ 5%, pH = 6–7, 4 °C, 16 h.

Scheme 3

Preparation of iodinated compounds (R/S)-18 (6-iodo-D/L-TIC(OH)) and (R/S)-21 (8-iodo-D/L-TIC(OH)). Reagents and conditions: (a) (i) paraformaldehyde, HBr 33% in AcOH, TFA, 80 °C, 1 h; (ii) paraformaldehyde, 80 °C, 15 h; (b) aq. HBr conc., EtOH, reflux, 16 h; (c) Zn, aq. HBr conc., EtOH, r.t., 2 h; (d) Pd/C 10%, H₂, Et₃N, EtOH, r.t., 28 h; (e) NIS, CH₂Cl₂, ultrasound, r.t., 30 s; (f) (i) aq. 1 M LiOH, THF, MeOH, r.t., 1 h; (ii) aq. HCl 1M, pH = 6/7, 4 °C, 2 h.

Scheme 4

Preparation of [¹²⁵I]iodo-L-TIC(OH) compounds ((S)-[¹²⁵I]14, (S)-[¹²⁵I]18 and (S)-[¹²⁵I]21). Reagents and conditions: (a) Boc₂O, Et₃N, DMAP, CH₂Cl₂, r.t., 16–20 h; (b) Sn₂Me₆, Pd(PPh₃)₄, 1,4-dioxane, reflux, 1.5 h for (S)-25 and (S)-26 or (i) 1.3 M iPrMgCl.LiCl, THF, −40 °C, 20 min; (ii) Me₃SnCl, THF, −40 °C, 3 h then r.t. for (S)-27; (c) (i) [¹²⁵I]NaI, CAT, EtOH, 1M PBS buffer, r.t., 5 min; (ii) aq. NaOH 10 M, 0 °C then r.t., 1 h; (iii) TFA, 0 °C then 60 °C, 30 min.

Figure 3

(A): UV-HPLC chromatograms (288 nm) of reference iodinated compounds (S)-14, (S)-18 and (S)-21; (B): Radioactivity-HPLC chromatograms of the corresponding radiotracers (S)-[¹²⁵I]14 ([¹²⁵I]5-iodo-L-TIC(OH)), (S)-[¹²⁵I]18 ([¹²⁵I]6-iodo-L-TIC(OH)) and (S)-[¹²⁵I]21 ([¹²⁵I]8-iodo-L-TIC(OH)) obtained after semi-preparative RP-HPLC purification and formulation. The radioactivity detector was connected in series after the UV detector accounting for a slight difference in retention times (≈0.3 min) observed between ¹²⁵I and ¹²⁷I products.

Scheme 5

Preparation of [¹⁸F]fluoro-L-TIC(OH) compounds ((S)-[¹⁸F]37, (S)-[¹⁸F]38 and (S)-[¹⁸F]39) and [¹⁹F]fluoro-D/L-TIC(OH) references ((R/S)-37, (R/S)-38 and (R/S)-39). Reagents and conditions: (a) Boc₂O, THF, aq. NaHCO₃, r.t., 2–6 h; (b) EtOCH₂Cl, DIPEA, THF, 40 °C, 16–22 h; (c) Sn₂Me₆, Pd(PPh₃)₄, 1,4-dioxane, reflux, 0.5–3 h for (R/S)-34 and (R/S)-35 or (i) 1.3 M iPrMgCl.LiCl, THF, −40 °C, 30 min; (ii) Me₃SnCl, THF, −40 °C, 1 h then r.t., 2 h for (R/S)-36; (d) (i) Ag₂O, NaHCO₃, NaOTf, F-TEDA-PF₆, acetone, 40–80 °C, 2–4 h; (ii) 7.2 M HCl in dioxane, r.t., 5 min; (iii) aq. 1M LiOH, MeOH, THF, r.t., 1–15 h; (e) (i) [¹⁸F]NaF, Cu(OTf)₂(py)₄, N,N-dimethylacetamide, 110 °C, 10 min, (ii) aq. HBr conc. 110 °C, 10 min.

Figure 4

(A): UV-HPLC chromatograms (288 nm) of reference fluorinated compounds (S)-37, (S)-38 and (S)-39; (B): Radioactivity-HPLC chromatograms of the corresponding radiotracers (S)-[¹⁸F]37 ([¹⁸F]5-fluoro-L-TIC(OH)), (S)-[¹⁸F]38 ([¹⁸F]6-fluoro-L-TIC(OH)) and (S)-[¹⁸F]39 ([¹⁸F]8-fluoro-L-TIC(OH)) obtained after semi-preparative RP-HPLC purification and formulation. The radioactivity detector was connected in series after the UV detector accounting for the slight difference in retention times (≈0.3 min) observed between ¹⁸F and ¹⁹F products.