III-3. Radiochemistry & Nuclear Chemistry

RIKEN Accel. Prog. Rep. 54 (2021)

RIKEN Accel. Prog. Rep. 54 (2021)

Complex formation of Rhenium-186 with lipophilic ligands—Comparison with technetium-99m—
I. O. Umeda,∗1 H. Haba,∗2 Y. Komori,∗2 H. Fujii,∗3 and T. Takahashi∗1Technetium-99m is the most used nuclide in diagnostic nuclear medical imaging because the energy ofits gamma-ray emission (140 keV) is ideal for imaging using gamma cameras, and it can be produced on
demand at medical facilities by using 99 Mo/99m Tc generators. Various lesions can be visualized when 99m Tclabeled radiopharmaceuticals accumulate at the lesion
site because of their unique mechanisms. In recentyears, radiotheranostics have received considerable attention because radionuclide-targeted treatments are
performed based on the imaging of the same target
area.1) Although 99m Tc-radiopharmaceuticals are specialized for diagnostic imaging, their speciﬁc lesion accumulation properties are attractive for radiotheranostics. Rhenium, a group 7 congeneric element of technetium, is assumed to have chemical properties similarto those of Tc. 186 Re is an ideal radiotheranostic nuclide because it is a beta-emitting nuclide, and it emits
gamma-ray associated with beta decay, whose energy
is suitable for radionuclide therapy and imaging. Thusfar, 186 Re has been produced by neutron irradiation in
nuclear reactors, and it is diﬃcult to obtain in Japan.
At the RIKEN RI beam factory (RIBF), we succeededin producing no-carrier-added, high-purity 186 Re using an accelerator-based ion beam irradiation. 99m Tcradiopharmaceuticals are complexes of 99m Tc and avariety of ligands. Further rhenium is expected toform complexes as an analog of Tc. Therefore, it isimportant to evaluate the complex forming ability ofRe. In this study, the complex formation of Re withlipophilic ligands was investigated using 186 Re produced at RIBF.
Rhenium-186 was produced in the 186 W(d, 2n)186 Rereaction. A 24-MeV deuteron beam delivered from theAVF cyclotron was irradiated onto a 186 WO3 pellet
target (isotope enrichment of 186 W: 99.79%; thickness:580 mg/cm2 ). After irradiation, 186 Re was puriﬁed
by chemical separation procedure.2) The aqueous solution of 186 Re-perrhenate in 0.01 M HCl (radioactivity concentration: 83.0 MBq/mL) was supplied.
MRP20 (N-(2(1H pyrolylmethyl)) N′ -(4-pentene-3one-2)) ethane-l, 2-diamine), ECD (ethyl cysteinatedimer), and BMEDA (n, n-bis(2-mercaptoethyl)n′ ,n′ -diethylethylene-diamine) were used as lipophilicchelating ligands. Stannous chloride was used as a
reductant and GH (sodium glucoheptonate) was used
as a stabilizer for 186 Re(V). The formation of 186 Religand complexes was evaluated using octanol/water
∗1
∗2
∗3

Kavli IPMU, the University of Tokyo
RIKEN Nishina Center
EPOC, National Cancer CenterFig. 1. Profiles of the paper chromatography of the reaction products of 186 Re with various lipophilic ligands.
Development solution: methanol or physiological saline
solution. Detection: Autoradiography using imagingplates.

extraction and paper chromatography, and it was developed in methanol or physiological saline.
We have been developing new radiopharmaceuticals by encapsulating various radionuclides in liposomes, which are capable DDS carriers.3) We used remote loading methods, to achieve a high concentration of radionuclides in liposomes, that is, a ligand exchange reaction across the liposomal membrane using
lipophilic and hydrophilic ligands. We successfully prepared 99m Tc- liposomes using MRP20 as a lipophilicligand. We ﬁrst examined the reaction between 186 Reand MRP20; sit was found that 186 Re and MRP20
did not form chelate complexes under the same conditions as 99m Tc. Therefore, the optimal conditions forthe reaction of 186 Re with lipophilic ligands MRP20,ECD, and BMEDA were investigated. 99m Tc couldform stable complexes with each of these three ligands under mild conditions. The complex formation
between 186 Re and these lipophilic ligands required 10times more reducing agent, higher reaction temperatures, and longer reaction times than those of 99m Tc.
Representative paper chromatography proﬁles of thesereaction products are shown in Fig. 1. 186 Re and ECD
formed a lipophilic ligand complex that moved close to
the solvent front in methanol. In the reaction of 186 Rewith BMEDA, the products were diﬀerent dependingon the reaction process. The products of process Aseemed to contain [186 ReO−
4 ] and the lipophilic complex. 186 Re and MRP20 could not form a complex evenwith these severe conditions, and their chromatogram
proﬁles were almost the same as those of [186 ReO−
4 ].
Based on these results, we speculate that 186 Re wasmore diﬃcult to reduce compared to 99m Tc analogues;
further, the reaction rate with ligands was slower than- 157 -1

III-3. Radiochemistry & Nuclear Chemistry

RIKEN Accel. Prog. Rep. 54 (2021)

that of 99m Tc. 186 Re seemed to be re-oxidizing withoxygen from the air back to [186 ReO−
4 ], which may
compete with the complex formation and inhibit thereaction.
It is believed that rhenium has similar chemical
properties to technetium, and it can be handled in thesame manner. However, the results of this study indicate that their chemical properties are very diﬀerent atleast in terms of the ligand-complex formation. Highlyconcentrated and stable 186 Re-labeling compounds arenecessary to promote radiotheranostics. The present
ﬁndings will help establish optimized labeling methods for 186 Re.
References1) K. Herrmann et al., Lancet Oncol. 21, e146 (2020).
2) N. Shigeta et al., J. Radioanal. Nucl. Chem. 205, 85 (1996).
3) I. Ogihara-Umeda et al., J. Nucl. Med. 37, 326 (1996).

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