TY - JOUR
T1 - Cold kit for prostate-Specific membrane antigen (PSMA) PET imaging
T2 - Phase 1 study of 68Ga-Tris (Hydroxypyridinone)-PSMA PET/CT in patients with prostate cancer
AU - Hofman, Michael S.
AU - Eu, Peter
AU - Jackson, Price
AU - Hong, Emily
AU - Binns, David
AU - Iravani, Amir
AU - Murphy, Declan
AU - Mitchell, Catherine
AU - Siva, Shankar
AU - Hicks, Rodney J.
AU - Young, Jennifer D.
AU - Blower, Philip J.
AU - Mullen, Gregory E.
N1 - Funding Information:
The study received funding from Theragnostics Ltd. Philip J. Blower and Gregory E. Mullen are named inventors on patents whose claims encompass the THP chelator. Jennifer D. Young is funded by the King’s College London and Imperial College London EPSRC Centre for Doctoral Training in Medical Imaging (EP/ L015226/1). We acknowledge support from the KCL and UCL Comprehensive Cancer Imaging Centre funded by CRUK and EPSRC in association with the MRC and DoH (England) and support from the NIRH Biomedical Research Centre awarded to the Guy’s and St. Thomas’ NHS Foundation Trust in partnership with the King’s College London and King’s College Hospital NHS Foundation Trust. No other potential conflict of interest relevant to this article was reported.
Funding Information:
This investigator-initiated prospective study was sponsored by the Peter MacCallum Cancer Centre, and ethics approval was given by the institutional review board. It was prospectively registered (Australian New Zealand Clinical Trials Registry No. 12615001324505). All subjects gave informed consent.
Publisher Copyright:
� Copyright 2018 SNMMI; all rights reserved.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 68Ga-labeled urea-based inhibitors of the prostate-specific membrane antigen (PSMA), such as 68Ga-labeled N,N’-bis(2-hydroxybenzyl)-ethylenediamine-N,N’-diacetic acid (HBED)-PSMA-11, are promising small molecules for targeting prostate cancer. A new radiopharmaceutical, 68Ga-labeled tris(hydroxypyridinone) (THP)-PSMA, has a simplified design for single-step kit-based radiolabeling. It features the THP ligand, which forms complexes with 68Ga31 rapidly at a low concentration, at room temperature, and over a wide pH range, enabling direct elution from a 68Ge/68Ga generator into a lyophilized radiopharmaceutical kit in 1 step without manipulation. The aim of this phase 1 study was to assess the safety and biodistribution of 68Ga-THP-PSMA. Methods: Cohort A comprised 8 patients who had proven prostate cancer and were scheduled to undergo prostatectomy; they had Gleason scores of 7–10 and a mean prostate-specific antigen level of 7.8 μg/L (range, 5.4–10.6 μg/L). They underwent PET/CT after the administration of 68Ga-THP-PSMA. All patients proceeded to prostatectomy (7 with pelvic nodal dissection). Dosimetry from multi-time-point PET imaging was performed with OLINDA/EXM. Cohort B comprised 6 patients who had positive 68Ga-HBED-PSMA-11 PET/CT scanning results and underwent comparative 68Ga-THP-PSMA scanning. All patients were monitored for adverse events. Results: No adverse events occurred. In cohort A, 6 of 8 patients had focal uptake in the prostate (at 2 h: average SUVmax, 5.1; range, 2.4–9.2) and correlative 31 staining of prostatectomy specimens on PSMA immunohistochemistry. The 2 68Ga-THP-PSMA scans with negative results had only 11/21 staining. The mean effective dose was 2.07E−02 mSv/MBq. In cohort B, 68Ga-THP-PSMA had lower physiologic background uptake than 68Ga-HBED-PSMA-11 (in the parotid glands, the mean SUVmax for 68Ga-THP-PSMA was 3.6 [compared with 19.2 for 68Ga-HBED-PSMA-11]; the respective corresponding values in the liver were 2.7 and 6.3, and those in the spleen were 2.7 and 10.5; P, 0.001 for all). In 5 of 6 patients, there was concordance in the number of metastases identified with 68Ga-HBED-PSMA-11 and 68Ga-THP-PSMA. Thirteen of 15 nodal abnormalities were subcentimeter. In 22 malignant lesions, the tumor-to-liver contrast with 68Ga-THP-PSMA was similar to that with 68Ga-HBED-PSMA (4.7 and 5.4, respectively; P 5 0.15), despite a higher SUVmax for 68Ga-HBED-PSMA than for 68Ga-THP-PSMA (30.3 and 10.7, respectively; P, 0.01). Conclusion: 68Ga-THP-PSMA is safe and has a favorable biodistribution for clinical imaging. Observed focal uptake in the prostate was localized to PSMA-expressing malignant tissue on histopathology. Metastatic PSMA-avid foci were also visualized with 68Ga-THP-PSMA PET. Single-step production from a Good Manufacturing Practice cold kit May enable rapid adoption.
AB - 68Ga-labeled urea-based inhibitors of the prostate-specific membrane antigen (PSMA), such as 68Ga-labeled N,N’-bis(2-hydroxybenzyl)-ethylenediamine-N,N’-diacetic acid (HBED)-PSMA-11, are promising small molecules for targeting prostate cancer. A new radiopharmaceutical, 68Ga-labeled tris(hydroxypyridinone) (THP)-PSMA, has a simplified design for single-step kit-based radiolabeling. It features the THP ligand, which forms complexes with 68Ga31 rapidly at a low concentration, at room temperature, and over a wide pH range, enabling direct elution from a 68Ge/68Ga generator into a lyophilized radiopharmaceutical kit in 1 step without manipulation. The aim of this phase 1 study was to assess the safety and biodistribution of 68Ga-THP-PSMA. Methods: Cohort A comprised 8 patients who had proven prostate cancer and were scheduled to undergo prostatectomy; they had Gleason scores of 7–10 and a mean prostate-specific antigen level of 7.8 μg/L (range, 5.4–10.6 μg/L). They underwent PET/CT after the administration of 68Ga-THP-PSMA. All patients proceeded to prostatectomy (7 with pelvic nodal dissection). Dosimetry from multi-time-point PET imaging was performed with OLINDA/EXM. Cohort B comprised 6 patients who had positive 68Ga-HBED-PSMA-11 PET/CT scanning results and underwent comparative 68Ga-THP-PSMA scanning. All patients were monitored for adverse events. Results: No adverse events occurred. In cohort A, 6 of 8 patients had focal uptake in the prostate (at 2 h: average SUVmax, 5.1; range, 2.4–9.2) and correlative 31 staining of prostatectomy specimens on PSMA immunohistochemistry. The 2 68Ga-THP-PSMA scans with negative results had only 11/21 staining. The mean effective dose was 2.07E−02 mSv/MBq. In cohort B, 68Ga-THP-PSMA had lower physiologic background uptake than 68Ga-HBED-PSMA-11 (in the parotid glands, the mean SUVmax for 68Ga-THP-PSMA was 3.6 [compared with 19.2 for 68Ga-HBED-PSMA-11]; the respective corresponding values in the liver were 2.7 and 6.3, and those in the spleen were 2.7 and 10.5; P, 0.001 for all). In 5 of 6 patients, there was concordance in the number of metastases identified with 68Ga-HBED-PSMA-11 and 68Ga-THP-PSMA. Thirteen of 15 nodal abnormalities were subcentimeter. In 22 malignant lesions, the tumor-to-liver contrast with 68Ga-THP-PSMA was similar to that with 68Ga-HBED-PSMA (4.7 and 5.4, respectively; P 5 0.15), despite a higher SUVmax for 68Ga-HBED-PSMA than for 68Ga-THP-PSMA (30.3 and 10.7, respectively; P, 0.01). Conclusion: 68Ga-THP-PSMA is safe and has a favorable biodistribution for clinical imaging. Observed focal uptake in the prostate was localized to PSMA-expressing malignant tissue on histopathology. Metastatic PSMA-avid foci were also visualized with 68Ga-THP-PSMA PET. Single-step production from a Good Manufacturing Practice cold kit May enable rapid adoption.
KW - 68Ga
KW - PET/CT
KW - Prostate cancer
KW - Prostate-specific membrane antigen
UR - http://www.scopus.com/inward/record.url?scp=85040513187&partnerID=8YFLogxK
U2 - 10.2967/jnumed.117.199554
DO - 10.2967/jnumed.117.199554
M3 - Article
C2 - 28986512
AN - SCOPUS:85040513187
SN - 0161-5505
VL - 59
SP - 625
EP - 631
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 4
ER -