18F-Labeled, PSMA-Targeted Radiotracers: Leveraging the Advantages of Radiofluorination for Prostate Cancer Molecular Imaging

Abstract

Prostate-specific membrane antigen (PSMA)-targeted PET imaging for prostate cancer with ⁶⁸Ga-labeled compounds has rapidly become adopted as part of routine clinical care in many parts of the world. However, recent years have witnessed the start of a shift from ⁶⁸Ga- to ¹⁸F-labeled PSMA-targeted compounds. The latter imaging agents have several key advantages, which may lay the groundwork for an even more widespread adoption into the clinic. First, facilitated delivery from distant suppliers expands the availability of PET radiopharmaceuticals in smaller hospitals operating a PET center but lacking the patient volume to justify an onsite ⁶⁸Ge/⁶⁸Ga generator. Thus, such an approach meets the increasing demand for PSMA-targeted PET imaging in areas with lower population density and may even lead to cost-savings compared to in-house production. Moreover, ¹⁸F-labeled radiotracers have a higher positron yield and lower positron energy, which in turn decreases image noise, improves contrast resolution, and maximizes the likelihood of detecting subtle lesions. In addition, the longer half-life of 110 min allows for improved delayed imaging protocols and flexibility in study design, which may further increase diagnostic accuracy. Moreover, such compounds can be distributed to sites which are not allowed to produce radiotracers on-site due to regulatory issues or to centers without access to a cyclotron. In light of these advantageous characteristics, ¹⁸F-labeled PSMA-targeted PET radiotracers may play an important role in both optimizing this transformative imaging modality and making it widely available. We have aimed to provide a concise overview of emerging ¹⁸F-labeled PSMA-targeted radiotracers undergoing active clinical development. Given the wide array of available radiotracers, comparative studies are needed to firmly establish the role of the available ¹⁸F-labeled compounds in the field of molecular PCa imaging, preferably in different clinical scenarios.

Keywords: 18F; 68Ga; PET; PSMA; Radiofluorine; prostate cancer; prostate-specific membrane antigen; radioligand therapy; theranostics.

Figure 1

Chemical structure of ¹⁸F-labeled radiotracers. [¹⁸F]DCFPyL (A), [¹⁸F]PSMA-1007 (B), [¹⁸F]CTT1057 (C), (D) [¹⁸F]JK-PSMA-7 and (E) [¹⁸F]AIF-PSMA-11. The urea backbone of (A), (B), (D) and (E) is marked in blue, while the phosphoramidate of [¹⁸F]CTT1057 in (C) is highlighted in orange. Modified from Behr et al. , © by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Figure 2

Head-to-head comparison of maximum intensity projections of [⁶⁸Ga]PSMA-11 and [¹⁸F]DCFPyL in a patient with rising levels of prostate-specific membrane antigen. For [¹⁸F]DCFPyL, additional PSMA-positive supradiapragmatic lesions are noted. Modified from Dietlein et al. , © the authors (2015), published under the terms of the Creative Commons Attribution 4.0 International supradiaphragmatic (http://creativecommons.org/licenses/by/4.0/).

Figure 3

Head-to-head comparison of [⁶⁸Ga]PSMA-11 vs. [¹⁸F]PSMA-1007 PET/CT. Biochemical relapse after prostatectomy, localized in the fossa of the seminal vesicle on the left. (A,D) early and (B,E) late [⁶⁸Ga]PSMA-11 PET/CT scans which showed an equivocal finding. The residual activity of [⁶⁸Ga]PSMA-11 3 hours p.i. was too low for a final interpretation (E). The additionally performed [¹⁸F]PSMA-1007 revealed the relapse with a PSMA overexpression, demonstrated on the maximal intensity projection (C) and on the coronal tomogram (F). The relapse showed a correlate on the low-dose CT (G).

Figure 4

Head-to-head comparison of [¹⁸F]CTT1057 PET study vs. standard of care bone scan vs. conventional CT. (A) [¹⁸F]CTT1057 maximum intensity projection (MIP) PET (left) with several matching PSMA avid osseous lesions on standard of care bone scan (right, yellow arrowheads), which can be seen on both imaging modalities. However, a PSMA avid lesion on [¹⁸F]CTT1057 in the skeleton has no clear bone scan correlate (blue arrow). (B) Axial [¹⁸F]CTT1057 PET (upper row, red arrowheads) highlights a 3 mm lymph node that is not enlarged by size criteria on conventional CT (lower row), but has marked [¹⁸F]CTT1057 uptake. In addition, further enlarged PSMA avid retroperitoneal lymph nodes can be detected (red arrowheads), along with PSMA avid lytic osseous metastases (green arrows).

Figure 5

Serial [¹⁸F]FSU-880 PET imaging. Whole-body distribution of [¹⁸F]FSU-880 in a patient suffering from prostate cancer with known metastatic disease. Maximum intensity projections of 5 serially performed [¹⁸F]FSU-880 PET studies (up to 2 h after radiotracer injection) are displayed. Uptake can be noted in a bone metastasis of the upper thoracic vertebrae, which has been already evident in PET 1, but can be even more clearly seen 2 h after administration of [¹⁸F]FSU-880 (PET 5, red arrow). Such findings further emphasize the importance of late imaging time-points in ¹⁸F-labeled PSMA imaging. Modified from Saga et al. , © the authors (2018), published under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ license.

Figure 6

Head-to-head comparison of [⁶⁸Ga]PSMA-11 vs. [¹⁸F]JK-PSMA-7. Whole-body distribution of [⁶⁸Ga]PSMA-11 (A) vs. [¹⁸F]JK-PSMA-7 (B) in the same patient. [⁶⁸Ga]PSMA-11 revealed only one PSMA-positive retroperitoneal paraaortal lymph node (blue arrow), whereas the [¹⁸F]JK-PSMA-7 PET/CT showed two PSMA-positive retroperitoneal lymph nodes (blue arrows). Modified from Dietlein et al. , © by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Figure 7

Scheme showing radiosynthesis procedures for recently introduced PSMA-targeting radiotracers. (A) [¹⁸F]CTT1057 (modified from et Behr al. , © by the Society of Nuclear Medicine and Molecular Imaging, Inc.), (B) [¹⁸F]FSU-880 (modified from Harada et al. , © by the Society of Nuclear Medicine and Molecular Imaging, Inc.), (C) [¹⁸F]JK-PSMA-7 (modified from Zlatopolskiy et al. , © by the Society of Nuclear Medicine and Molecular Imaging, Inc.) and (D) [¹⁸F]AlF-PSMA-11 (modified from Lütje et al. , © by the Society of Nuclear Medicine and Molecular Imaging, Inc.). DIPEA = diisopropylethylamine.