PET imaging of ¹¹C-labeled thiamine tetrahydrofurfuryl disulfide, vitamin B₁ derivative: First-in-human study

Vitamine B₁ thiamine is an essential component for glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is more absorbent compared to readily-available water-soluble thiamine salts since it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions were not clarified yet. Recently, ¹¹C-labeled thiamine and TTFD were synthesized by our group, and their pharmacokinetics were investigated by PET imaging in normal rats. In this study, to clarify the whole body pharmacokinetics of [¹¹C]TTFD in human healthy volunteers, we performed first-in-human PET imaging study with [¹¹C]TTFD, along with radiation dosimetry of [¹¹C]TTFD in humans.

Synthesis of [¹¹C]TTFD was improved for clinical study. Dynamic whole-body PET images were acquired on three young male normal subjects after intravenous injection of [¹¹C]TTFD. VOIs were defined for source organs on the PET images to measure time-course of [¹¹C]TTFD uptake as percentage injected dose and the number of disintegrations for each organ. Radiation dosimetry was calculated with OLINDA/EXM.

We succeeded in developing the improved synthetic method of [¹¹C]TTFD for the first-in-human PET study. In the whole body imaging, uptake of [¹¹C]TTFD by various tissues was almost plateaued at 10 min after intravenous injection, afterward gradually increased for the brain and urinary bladder (urine). %Injected dose was high in the liver, kidney, urinary bladder, heart, spine, brain, spleen, pancreas, stomach, and salivary glands, in this order. %Injected dose per gram of tissue was high also in the pituitary. By dosimetry, the effective radiation dose of [¹¹C]TTFD calculated was 5.5 μSv/MBq (range 5.2-5.7).

Novel synthetic method enabled clinical PET study with [¹¹C]TTFD, which is a safe PET tracer with a dosimetry profile comparable to other common ¹¹C-PET tracers. Pharmacokinetics of TTFD in the pharmacological dose and at different nutritional states could be further investigated by future quantitative PET studies. Noninvasive in vivo PET imaging for pathophysiology of thiamine-related function may provide diagnostic evidence of novel information about vitamin B₁ deficiency in human tissues.