First-in-Human Biodistribution and Dosimetry of [¹¹C]Trimethoprim

Trimethoprim (TMP) is a reversible inhibitor of the prokaryotic enzyme dihydrofolate reductase (DHFR) used for the treatment or prophylaxis of bacterial infections. [¹¹C]trimethoprim ([¹¹C]TMP) is a positron emission tomography (PET) imaging isotopologue of TMP. TMP binds with 30,000-fold greater affinity to bacterial DHFR over the homologous mammalian enzyme in vitro, suggesting [¹¹C]TMP may selectively accumulate in tissues with cells expressing bacterial DHFR. This study characterizes the biodistribution and dosimetry of [¹¹C]TMP, informing its use in imaging bacterial infections and tracking mammalian cells expressing eDHFR as a reporter gene.

Four males with suspected infection, aged 59 ± 10 years old (mean ± SD) received 3 serial PET/CT scans after injection of 346 ± 305 MBq (range 129-797 MBq) of [¹¹C]TMP. Organ activities were measured in MIM v6.7, including brain, kidneys, spleen, liver, heart, lungs, bladder, intestines, gallbladder, pancreas, thyroid, and red marrow. Dosimetry calculations were performed in Olinda | EXM v1.1. Additionally, a dynamic whole-body PET/CT scan was performed on a separate participant. The associated trial was registered as NCT03424525.

[¹¹C]TMP injections were well tolerated with no adverse events. The average injected activity of 346 MBq of [¹¹C]TMP yielded an estimated average dose of 4.9 mSv in the highest uptake organ (liver), 4.1 mSv in the spleen, and an effective dose of 1.6 mSv. Suspected sites of infection displayed uptake above background.

[¹¹C]TMP PET was safe and demonstrated low background uptake in most tissues. The data suggests feasibility for evaluation of varied bacterial infections, including musculoskeletal infections. Absorbed doses allow multiple [¹¹C]TMP PET scans each year within Radioactive Drug Research Committee (RDRC) limits, potentially enabling monitoring of infections and treatment response.