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The aim of this study was to develop a treatment protocol for Ac-PSMA-617 α-radiation therapy in advanced-stage, metastatic castration-resistant prostate cancer patients with prostate-specific membrane antigen (PSMA)-positive tumor phenotype. A dosimetry estimate was calculated on the basis of time-activity curves derived from serially obtained Lu-PSMA-617 scans extrapolated to the physical half-life ofAc, assuming instant decay of unstable daughter nuclides. Salvage therapies empirically conducted with 50 ( = 4), 100 ( = 4), 150 ( = 2), and 200 kBq/kg ( = 4) of Ac-PSMA-617 were evaluated retrospectively regarding toxicity and treatment response. Eight of 14 patients received further cycles in either 2- or 4-mo intervals with identical or deescalated activities. Dosimetry estimates for 1 MBq of Ac-PSMA-617 assuming a relative biologic effectiveness of 5 revealed mean doses of 2.3 Sv for salivary glands, 0.7 Sv for kidneys, and 0.05 Sv for red marrow that are composed of 99.4% α, 0.5% β, and 0.1% photon radiation, respectively. In clinical application, severe xerostomia became the dose-limiting toxicity if treatment activity exceeded 100 kBq/kg per cycle. At 100 kBq/kg, the duration of prostate-specific antigen decline was less than 4 mo, but if therapy was repeated every 2 mo patients experienced additive antitumor effects. Treatment activities of 50 kBq/kg were without toxicity but induced insufficient antitumor response in these high-tumor-burden patients. Remarkable antitumor activity by means of objective radiologic response or tumor marker decline was observed in 9 of 11 evaluable patients. For advanced-stage patients, a treatment activity of 100 kBq/kg of Ac-PSMA-617 per cycle repeated every 8 wk presents a reasonable trade-off between toxicity and biochemical response.

QSPECT reconstruction appears to be useful for reduction of camera-specific intersubject variability of [(123)I]FP-CIT SPECT in multisite and single-site multicamera settings. Whole brain excluding striatal binding as the reference provides more stable quantitative estimates than occipital or cerebellar binding.

Purpose Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [18F] fluspidine and [18F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD. Methods Using [18F] fluspidine PET (300 MBq, 0–90 min), 11 male HVs (pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (pridopidine 90 mg) were investigated twice, without and 2 h after single dose of pridopidine. Using [18F] fallypride PET (200 MBq, 0–210 min), four male HVs were studied without and 2 h following pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot. Results S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%). Conclusions Our PET findings indicate that at clinically relevant single dose of 90 mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine’s mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.

Because of different physical properties, the β-emitters 177 Lu and 90 Y offer specific radiologic-biologic advantages in dedicated clinical situations. Our objective was to introduce 90 Y-labeled prostatespecific membrane antigen (PSMA)-617 to clinical application, providing additional avenues for personalized medicine. Here, we present our dosimetry estimate for 90 Y-PSMA-617, report first clinical experiences, and discuss the advantages and drawbacks of varying the β-emitter in PSMA-targeting radioligand therapy. Methods: To approximate radiation dosimetry, 4 patients with metastatic castration-resistant prostate cancer underwent serially performed imaging up to 1 wk after 177 Lu-PSMA-617 therapy. Time-activity curves were extrapolated to the half-life of 90 Y, and OLINDA was used to calculate the dosimetry estimate. In clinical practice, 11 patients with PSMApositive lymph-nodal bulk disease were stratified to receive 90 Y-PSMA-617 radioligand therapy (mean, 3.2 GBq; range, 2.8-3.7 GBq); afterward, safety lab tests, prostate-specific antigen (PSA) response, and clinical findings were thoroughly followed. Results: The projected dosimetry for 90 Y-PSMA-617 estimated a mean kidney dose of 3.47 ± 1.40 Gy/GBq, red marrow dose of 0.11 ± 0.04 Gy/GBq, and salivary gland dose of 5.57 ± 1.34 Gy/GBq; randomly chosen metastases were approximated with 22.8 ± 16.10 Gy/GBq. The observed acute hematologic toxicity (5 cases of leukopenia and 2 of thrombocytopenia, all grade 1 or 2) and clinical side effects (2 cases of transient xerostomia and 1 of nausea, all grade 1 or 2), as well as PSA response (any PSA response, 7/11 patients; .50% PSA decline, 5/11 patients), were comparable to 177 Lu-PSMA-617 literature data. Conclusion: A factor 3-4 lower treatment activity for 90 Y-PSMA-617 translates into a comparable dosimetry estimate and clinical findings similar to those of 177 Lu-PSMA-617. However, safety was demonstrated only for patients with oligometastatic disease. Further studies are needed to evaluate its potential in patients with more disseminated bone involvement or visceral metastasis.