Optimal detection of the neutron capture therapy agent borocaptate sodium (BSH): A comparison between 1H and 10B NMR

Abstract

Boron Neutron Capture Therapy (BNCT), an experimental binary cancer treatment modality, requires selective targeting of 10B containing compounds to tumors. One of the compounds under evaluation in an EORTC phase I trial, and used in Japan for patient treatments for many years, is borocaptate sodium (BSH, also known as sulfhydril boron hydride). To optimize the clinical applications, a noninvasive method is needed to monitor the distribution of the boron compound, and NMR may offer such a possibility. A comparison between the relative sensitivities for detecting BSH by 10B or 1H NMR was conducted at two magnetic field strengths: 2 and 4.7 T. At each field strength, similar-sized radio frequency (rf) coils were used for both nuclei. Theoretical predictions for the intrinsic signal to noise (S/N) advantage of 1H over 10B detection vary between a factor of 5.4 and a factor of 28.9, depending on whether the effective resistance is dominated by coil losses or sample losses. Our tests, conducted on relatively small aqueous samples, which loaded the coils less than expected for animal or human subjects, resulted nevertheless in advantage factors close to the lower limit of this range. The measured S/N detection advantage factors for 1H were about 5.2 at 4.7 T, using a dedicated 1H coil, and 7.7 at 2 T, where the measurements were conducted with a double-tuned coil. However, when predicting the expected performance for in vivo MRS or MRI, one should bear in mind that proton detection has to be conducted by spectral-editing pulse sequences with an inherent S/N loss by at least a factor of 2, and that the T1 relaxation time for 10B in BSH is about 30 times shorter than the 1HT1 value. In view of these considerations, direct 10B detection could well be the preferred strategy for MRI/MRS of BSH in vivo.

Biomedical applications of10B and11B NMR

“…44 A theoretical and practical evaluation of the relative merits of 10 B and 1 H NMR for the detection of BSH in-vivo was conducted. 40 The results of that study showed that the sensitivity advantage of 1 H detection is not as obvious as intuitively assumed. Fundamental considerations, based on the spin quantum number I and the gyromagnetic ratio , predict an enhancement factor of 28.9 in favor of 1 H in the limit of noise dominated by coil resistance (which applies to small non-conducting samples), but when the noise is dominated by the sample itself, this enhancement factor is reduced to 5.4.…”

“…Thus, the apparent transverse relaxation rate is slower than that of 11 B under the same circumstances, which was also corroborated by theoretical simulation. 40 Each molecule of BSH has 11 hydrogen atoms which are directly attached to boron, and in the case of 10 B, the scalar coupling constant is J ¼ 43 Hz. Therefore, it seems reasonable to somehow benefit from this interaction for the detection of 10 B-enriched BSH molecules, which was first proposed by De Luca et al 41 The most sensitive realization of this concept should involve a pulse sequence, in which the proton magnetization is excited and detected after a 10 B-editing filter, which passes only the signal from hydrogens coupled to 10 B.…”

“…Fundamental considerations, based on the spin quantum number I and the gyromagnetic ratio , predict an enhancement factor of 28.9 in favor of 1 H in the limit of noise dominated by coil resistance (which applies to small non-conducting samples), but when the noise is dominated by the sample itself, this enhancement factor is reduced to 5.4. Experimental measurements yielded values of 5.2 at 4.7 T, and 7.7 at 2.0 T. 40 However, the sensitivity advantage for 1 H is further eroded by various spectral editing procedures that are inevitable in order to distinguish the small 1 H proton signal from BSH from a huge background. Moreover, the much shorter T 1 relaxation time for 10 B permits faster pulse repetition rates, thereby improving the S/N per unit time for 10 B.…”

In vivo imaging of the neutron capture therapy agent BSH in mice using 10B MRI

“…So far, the in vivo MR imaging of BSH was demonstrated only for the natural abundance compound (5), using 11 B detection ( 11 B has 80% natural abundance). This approach is obviously not suitable for clinical applications, where the boronated molecules are enriched in 10 B to over 95%. It was always assumed that direct 10 B detection would not be sensitive enough for MRI of BNCT agents, due to the low gyromagnetic ratio of 10 B, and therefore considerable efforts were devoted to the development and implementation of indirect detection methods.…”

“…Boron neutron capture therapy (BNCT) is based on the high cross section of 10 B for capturing thermal neutrons (1,2). This nuclear reaction yields alpha particles and recoiling lithium nuclei, both with high linear energy transfer (LET) and relatively short spatial range (ϳ10 m).…”