[18F]-JK-PSMA-7 PET/CT Under Androgen Deprivation Therapy in Advanced Prostate Cancer

Purpose

PSMA imaging is frequently used for monitoring of androgen deprivation therapy (ADT) in prostate cancer. In a previous study, [¹⁸F]-JK-PSMA-7 exhibited favorable properties for tumor localization after biochemical recurrence. In this retrospective study, we evaluated the performance of [¹⁸F]-JK-PSMA-7 under ADT.

Procedures

We examined the performance of [¹⁸F]-JK-PSMA-7 in 70 patients (first cohort) with increasing or detectable PSA values under ADT (PSA < 2 ng/ml for 21/70 patients). We further analyzed 58 independent patients with PSA levels < 2 ng/ml under ADT, who were imaged with [⁶⁸Ga]PSMA-11 or [¹⁸F]DCFPyL (second cohort). Finally, we compared detection rates between [¹⁸F]-JK-PSMA-7, [⁶⁸Ga]PSMA-11, and [¹⁸F]DCFPyL.

Results

In the first cohort, we detected [¹⁸F]-JK-PSMA-7-positive lesions in 63/70 patients. In patients with PSA levels ≥ 2 ng/ml, the detection rate was 100 % (49/49). In patients with PSA < 2 ng/ml, the detection rate was significantly lower (66.7 %, 14/21, p = 9.7 × 10^?5) and dropped from 85.7 % (12/14, PSA levels between 0.3 and 2.0 ng/ml) to 28.6 % (2/7) for PSA levels < 0.3 ng/ml (p = 1.73 × 10^?2). In the second cohort (PSA < 2 ng/ml), the detection rate was 79.3 % (46/58) for [⁶⁸Ga]PSMA-11 or [¹⁸F]DCFPyL. Again, the detection rate was significantly higher (p = 1.1 × 10^?2) for patients with PSA levels between 0.3 and 2.0 ng/ml (87.0 %, 40/46) relative to those with PSA levels < 0.3 ng/ml (50 %, 6/12). No significant difference was found between [¹⁸F]-JK-PSMA-7 and [⁶⁸Ga]PSMA-11 or [¹⁸F]DCFPyL in patients with PSA levels < 2 ng/ml (p = 0.4295).

Conclusion

[¹⁸F]-JK-PSMA-7 PET showed a high detection rate in patients with PSA levels ≥ 0.3 ng/ml under ADT. The lower PSA threshold of 0.3 ng/ml for high detection rates was consistent across the three PSMA ligands. Thus, PSMA imaging is suitable for clinical follow-up of patients with increasing PSA levels under ADT.

     

Hedgehog signaling sensitizes Glioma stem cells to endogenous nano-irradiation

The existence of therapy resistant glioma stem cells is responsible for the high recurrence rate and incurability of glioblastomas. The Hedgehog pathway activity plays an essential role for self-renewal capacity and survival of glioma stem cells. We examined the potential of the Sonic hedgehog ligand for sensitizing of glioma stem cells to endogenous nano-irradiation. We demonstrate that the Sonic hedgehog ligand preferentially and efficiently activats glioma stem cells to enter the radiation sensitive G2/M phase. Concomitant inhibition of de novo thymidine synthesis with fluorodeoxyuridine and treatment with the Auger electron emitting thymidine analogue 5-[I-125]-Iodo-4′-thio-2′-deoxyuridine ([I-125]ITdU) leads to a fatal nano-irradiation in sensitized glioma stem cells. Targeting of proliferating glioma stem cells with DNA-incorporated [I-125]ITdU efficiently invokes the intrinsic apoptotic pathway despite active DNA repair mechanisms. Further, [I-125]ITdU completely inhibits survival of glioma stem cells in vitro. Analysis of non-stem glioblastoma cells and normal human astrocytes reveals that glioma stem cells differentially respond to Sonic hedgehog ligand. These data demonstrate a highly efficient and controllable single-cell kill therapeutic model for targeting glioma stem cells.     

Auger electron emitter against multiple myeloma--targeted endo-radio-therapy with 125I-labeled thymidine analogue 5-iodo-4'-thio-2'-deoxyuridine

Introduction

Multiple myeloma (MM) is a plasma cell malignancy characterized by accumulation of malignant, terminally differentiated B cells in the bone marrow. Despite advances in therapy, MM remains an incurable disease. Novel therapeutic approaches are, therefore, urgently needed. Auger electron-emitting radiopharmaceuticals are attractive for targeted nano-irradiation therapy, given that DNA of malignant cells is selectively addressed. Here we evaluated the antimyeloma potential of the Auger electron-emitting thymidine analogue ¹²⁵I-labeled 5-iodo-4′-thio-2′-deoxyuridine ([¹²⁵I]ITdU).

Methods

Cellular uptake and DNA incorporation of [¹²⁵I]ITdU were determined in fluorodeoxyuridine-pretreated KMS12BM, U266, dexamethasone-sensitive MM1.S and -resistant MM1.R cell lines. The effect of stimulation with interleukin 6 (IL6) or insulin-like growth factor 1 (IGF1) on the intracellular incorporation of [¹²⁵I]ITdU was investigated in cytokine-sensitive MM1.S and MM1.R cell lines. Apoptotic cells were identified using Annexin V. Cleavage of caspase 3 and PARP was visualized by Western blot. DNA fragmentation was investigated using laddering assay. Therapeutic efficiency of [¹²⁵I]ITdU was proven by clonogenic assay.

Results

[¹²⁵I]ITdU was shown to be efficiently incorporated into DNA of malignant cells, providing a promising mechanism for delivering highly toxic Auger radiation emitters into tumor DNA. [¹²⁵I]ITdU had a potent antimyeloma effect in cell lines representing distinct disease stages and, importantly, in cell lines sensitive or resistant to the conventional therapeutic agent, but was not toxic for normal plasma and bone marrow stromal cells. Furthermore, [¹²⁵I]ITdU abrogated the protective actions of IL6 and IGF1 on MM cells. [¹²⁵I]ITdU induced massive damage in the DNA of malignant plasma cells, which resulted in efficient inhibition of clonogenic growth.

Conclusion

These studies may provide a novel treatment strategy for overcoming resistance to conventional therapy in multiple myeloma.     

C-(4-[18F]fluorophenyl)-N-phenyl nitrone: A novel 18F-labeled building block for metal free [3+2]cycloaddition

Radiofluorination via [3+2]-nitrone-alkene cycloaddition was studied using the model reaction between (18)F-labeled C-(4-fluorophenyl)-N-phenyl nitrone ([(18)F]1) and substituted maleimides 2a-c. [(18)F]1 was prepared in RCY of 73.6±5.8% and radiochemical purity of >95%. Cycloaddition of [(18)F]1 to 2a in toluene at 80°C and in EtOH at 110°C gave the respective isoxazolidine [(18)F]5a in >80% RCY at 10min reaction time. Reaction between [(18)F]1 and 2b, c also went smoothly to afford the respective cycloaddition products in high radiochemical yields.     

Minimalist approach meets green chemistry: Synthesis of 18F‐ labeled (hetero)aromatics in pure ethanol

The application of toxic solvents and additives is inevitable for most of the described protocols for ¹⁸F‐labeling. Herein, a novel “green” procedure for nucleophilic aromatic radiofluorination of highly activated (hetero)aromatic substrates in pure EtOH is described. Using this method a series of ¹⁸F‐labeled (hetero)arenes have been synthesized in radiochemical yields (RCYs) of up to 97%.     

123I-ITdU-mediated nanoirradiation of DNA efficiently induces cell kill in HL60 leukemia cells and in doxorubicin-, beta-, or gamma-radiation-resistant cell lines.

Resistance to radiotherapy or chemotherapy is a common cause of treatment failure in high-risk leukemias. We evaluated whether selective nanoirradiation of DNA with Auger electrons emitted by 5-(123)I-iodo-4'-thio-2'-deoxyuridine ((123)I-ITdU) can induce cell kill and break resistance to doxorubicin, beta-, and gamma-irradiation in leukemia cells. METHODS: 4'-thio-2'-deoxyuridine was radiolabeled with (123/131)I and purified by high-performance liquid chromatography. Cellular uptake, metabolic stability, DNA incorporation of (123)I-ITdU, and the effect of the thymidylate synthase (TS) inhibitor 5-fluoro-2'-deoxyuridine (FdUrd) were determined in HL60 leukemia cells. DNA damage was assessed with the comet assay and quantified by the olive tail moment. Apoptosis induction and irradiation-induced apoptosis inhibition by benzoylcarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD.fmk) were analyzed in leukemia cells using flow cytometry analysis. RESULTS: The radiochemical purity of ITdU was 95%. Specific activities were 900 GBq/micromol for (123)I-ITdU and 200 GBq/micromol for (131)I-ITdU. An in vitro cell metabolism study of (123)I-ITdU with wild-type HL60 cells demonstrated an uptake of 1.5% of the initial activity/10(6) cells of (123)I-ITdU. Ninety percent of absorbed activity from (123)I-ITdU in HL60 cells was specifically incorporated into DNA. (123)I-ITdU caused extensive DNA damage (olive tail moment > 12) and induced more than 90% apoptosis in wild-type HL60 cells. The broad-spectrum inhibitor of caspases zVAD-fmk reduced (123)I-ITdU-induced apoptosis from more than 90% to less than 10%, demonstrating that caspases were central for (123)I-ITdU-induced cell death. Inhibition of TS with FdUrd increased DNA uptake of (123)I-ITdU 18-fold and the efficiency of cell kill about 20-fold. In addition, (123)I-ITdU induced comparable apoptotic cell death (>90%) in sensitive parental leukemia cells and in leukemia cells resistant to beta-irradiation, gamma-irradiation, or doxorubicin at activities of 1.2, 4.1, 12.4, and 41.3 MBq/mL after 72 h. This finding indicates that (123)I-ITdU breaks resistance to beta-irradiation, gamma-irradiation, and doxorubicin in leukemia cells. CONCLUSION: (123)I-ITdU-mediated nanoirradiation of DNA efficiently induced apoptosis in sensitive and resistant leukemia cells against doxorubicin, beta-irradiation, and gamma-irradiation and may provide a novel treatment strategy for overcoming resistance to conventional radiotherapy or chemotherapy in leukemia. Cellular uptake and cell kill are highly amplified by inhibiting TS with FdUrd.     

One pot radiofluorination of a new potential PSMA ligand [Al18F]NOTA‐DUPA‐Pep

Up to now, many radiolabeled ligands targeting prostate‐specific membrane antigen (PSMA) have been synthesized. To carry out radiofluorinations, there have been several approaches mainly involving two steps of radiosynthesis. However, in case of labelings with high activities, one radiosynthetic step (‘one pot synthesis’) is highly desirable. As an alternative, radiofluorinations of peptides coupled to the NOTA complex via Al¹⁸F appear to be very promising, both in terms of feasible labelling procedure and stability in vivo. Therefore, in the present study, we synthesized a new PSMA‐ligand, that is, NOTA‐DUPA‐Pep, labeled with Al¹⁸F and examined the reaction kinetics in dependence on temperature, time, concentration of precursor, and AlCl₃ solution. Highest radiochemical yields of 83 ± 1.1% were obtained at 105 °C after 15 min of reaction time. At the end of synthesis, [Al¹⁸F]NOTA‐DUPA‐Pep was prepared with a radiochemical purity of ≥98% with an overall yield of 79 ± 0.7% (n = 3) (decay uncorrected) within 55 min. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis and biodistribution of 3'-fluoro-5-[(131)I]iodo-2'-deoxyuridine: a comparative study of [(131)I]FLIdU and [(18)F]FLT

The radioiodinated 3'-fluorothymidine (FLT) analogue 3'-fluoro-5-[(131)I]iodo-2'-deoxyuridine ([(131)I]FLIdU) was synthesized, with iodine mimicking the methyl group of pyrimidine. [(131)I]FLIdU was accessible by direct electrophilic iodination using Iodogen as oxidant. Optimized amounts of the oxidant allowed radiochemical yields of about 70% after a reaction time of 10 min in an aqueous buffer medium at 90 degrees C. The uptake of [(131)I]FLIdU in a DoHH2 leukemia xenograft mouse model and in healthy mice revealed moderate FLIdU accumulation, followed by a significant washout of activity in proliferating tissues such as splenic and tumor tissues. In contrast, intraperitoneal coinjection with [(18)F]FLT showed high uptake and high activity retention up to 2 h, in both splenic and tumor tissues. Uptake in stomach tissues and increasing fractions of [(131)I]iodide in urine indicated metabolic instability of [(131)I]FLIdU due to rapid deiodination. Therefore, [(131)I]FLIdU alone does not seem to be a promising compound, neither for diagnostic imaging nor for potential therapeutic applications.