The accurate assessment of the absorbed radiation dosimetry of [11C]TZ1964B is an important preliminary step before translation to clinical applications of this PET radiopharmaceutical. The extrapolated human dosimetry measures from the PET based measurements of absorbed radioactivity in nonhuman primates after intravenous administration of [11C]TZ1964B is reported here. The principal findings in addition to the selective striatal uptake previously reported by our group [15, 16] were the widespread biodistribution of the radiotracer with liver being the critical organ and the relatively low exposure to radiosensitive organs; the gradual clearance from the liver and accumulation in the gallbladder were suggestive of hepatobiliary clearance.

A nonhuman primate model of absorbed radiation measures becomes particularly relevant in the setting of hepatic metabolism of the radiotracer, as the gallbladder may receive and accumulate its metabolites and potentially be a critical organ with high radiation burden. In fact, the gradual clearance from the liver was also noted in prior biodistribution study of [11C]TZ1964B in rats[13]. However, rats lack gallbladder making that animal model inadequate for estimating human dose exposure and justifies the choice of nonhuman primates that closely resembles human physiology for this dosimetry analysis.

The liver is indeed the critical organ for [11C]TZ1964B; the tissue biodistribution raises the possibility of in vivo hepatic degradation. The absorbed radiation dose estimates for liver were 53.3 μGy/MBq for males and 52.9 μGy/MBq in females. Other organs with high radiation dose were the gallbladder and spleen, with maximal absorbed radiation dose estimates of 35.9 and 35.4 μGy/MBq respectively. The maximal radiation dose estimate for the heart wall was 10.9 μGy/MBq.

Prior mRNA expression profile of PDE10A demonstrated strikingly selective gene expression in the brain especially in the caudate that was almost 20 fold-higher than multiple peripheral tissues in humans [24]. Of the peripheral tissues, highest levels of PDE10 mRNA was present in the thyroid; with detectable expression levels in kidneys, heart and lungs. The PDE10A expression was significantly lower in other peripheral tissues tested including liver and spleen [24]. Importantly, relatively low exposure to thyroid (1.93 μGy/MBq), a radiosensitive organ was noted in our analysis. The PDE10A expression pattern could account for the relatively high absorbed radiation noted in the heart wall (in addition to the exposure to radioactivity due to high blood volume in the heart chambers) but does not quite explain the relatively high estimates in the liver, gallbladder and spleen. The gradual clearance from the liver and accumulation of the radiotracer in the gallbladder (in the setting of relatively low absorbed radiation in kidneys and lack of accumulation in the bladder) were suggestive of predominantly hepatobiliary clearance rather than renal elimination of this radiotracer. This could potentially contribute to the high radiation dose received by the liver. On the contrary, the rapid clearance from the spleen closely reflected the clearance from the blood compartment and hence the splenic perfusion appears to be largely responsible for the relatively high radiation dose to the spleen. It would also be important to note as elaborated in the Methods section, our approach to generating the spleen VOI s is a very conservative one and likely overestimates the absorbed radiation dose in the spleen. Even though there is selective accumulation in the brain especially in the striatum, the brain overall receives a relatively modest radiation dose (4.4 μGy/MBq), possibly due to the modest partitioning of the compound into the brain. Radiation dose estimates for the kidneys (11.9 μGy/MBq) and urinary bladder (1.8 μGy/MBq) argue against predominant renal clearance of [11C]TZ1964B.

Significantly greater (around twice as much) absorbed radiation dose estimate for the gallbladder were noted in female compared to males. While pharmacologic (e.g. dosage of ketamine, glycopyrrolate with anticholinergic properties, time interval between tracer injection and induction of anesthesia etc.) and non-pharmacologic (duration of starvation, variances in diet) factors could contribute to such discrepancy, close scrutiny did not reveal significant differences in any of these confounding variables across studies. Of note, the female macaque received ondansetron (5HT3 receptor antagonist) during scan session#2 due to emesis after induction of anesthesia. Ondansetron was not administered in any of the other animals during the scan sessions. Although the data is not entirely clear, limited evidence in the literature suggests ondansetron could inhibit gallbladder emptying [25, 26] and this may have contributed to the enhanced accumulation of radioactivity in the gallbladder (time-activity curve from scan#2 in the female (Fig. 2) demonstrated continued accumulation of radiotracer up to around 170 min) well in excess of what was evidenced in scan session#1 in the same female monkey. Speculatively, significantly greater age at the time of scan#2 (Table 4) obtained 3 years later, could also have potentially contributed to the variances in the gallbladder uptake between scan sessions from the same female. However, even the larger dose calculation still is substantially below guidelines for non-radiosensitive organs. Furthermore, different calculations for gallbladder uptake make almost no differences in the effective dose estimates. Similarly, almost two times higher time-integrated activity and radiation dose estimates were evidenced for the spleen in the female compared to the males. Unlike the gallbladder however, there was significant concordance between the two scans in the same female macaque obtained 3 years apart. Any definitive inferences regarding significant sex differences are precluded by the fact that the same female monkey was scanned twice in the current study. This could be a unique physiological variance in this particular macaque. A much larger “n” could potentially clarify the differences across sexes reported here but this is not the goal of the current dosimetry analysis. More importantly this study demonstrates the significantly greater measures in the female are also well and truly within the allowed absorbed dose limits.

For a maximum absorbed dose of 50 mSv to the critical organ as per FDA 21 CFR 371.1 regulations (< 50 mSv to any organ, < 30 mSv to radiation sensitive organs), our estimates indicate that doses up to 938 MBq of [11C]TZ1964B can be administered to human subjects. The relatively low exposure to the radiosensitive organs including bone marrow, thyroid, gonads etc. (all calculated absorbed doses < 2.5 mSv) safely permits this total injected dose.

Due to its shorter half-life, [11C]TZ1964B could be utilized for multiple scans in the same subject on the same day. Given the liver is a critical organ, it becomes imperative to exercise caution when combining with another radiopharmaceutical with predominantly hepatobiliary clearance. The effective dose for [11C]TZ1964B closely resembled the mean effective dose of 21 other 11C-labeled tracers (range 3.0–6.8 μSv/MBq) [27]. Importantly however, close scrutiny of nine 11C-labeled tracers with available dosimetry analyses in monkeys and humans, the effective dose extrapolated from monkeys (7.3 ± 1.6 μSv/MBq) were generally noted to overestimate the actual measured effective dose in humans (5.7 ± 1.2 μSv/MBq) and monkeys had a higher liver uptake[27]. This sets the stage for further human PET studies with [11C]TZ1964B to sort out these issues including the sex-differences reported here.