Philippus Elsinga

11C-Choline Positron Emission Tomography for the Evaluation after Treatment of Localized Prostate Cancer

RATIONALE The evaluation of the efficacy of the treatment of men with prostate cancer is largely based on post treatment levels of PSA. An increase in PSA or biochemical recurrence is the first sign of recurrent disease and precedes a clinically detectable recurrence by months to years. Digital rectal examination and conventional imaging techniques are not sensitive to detect a local recurrence. A metabolic imaging technique, which is not dependent on anatomical distortions, could be of use. In this study we investigated 11C-choline positron emission tomography (PET) for the evaluation after treatment of localized prostate cancer. METHODS Thirty-six patients with localized prostate cancer, treated by either radical prostatectomy (n=20) or by external beam radiotherapy (n=16) were studied with 11C-choline PET. The results of PET were compared with the results of histology and with clinical follow up. RESULTS Fourteen patients had no biochemical failure after therapy. 11C-choline PET was true negative in 14/14 patients. Twenty-two patients had a biochemical failure. In the radical prostatectomy patients 11C-choline PET was true positive in 5/13 (38%) cases. In the external beam radiotherapy patients 11C-choline PET was true positive in 7/9 (78%). The recurrent tumor was confirmed by biopsy or by bone scan in eleven of the twelve true positive patients. In ten patients with a negative 11C-choline PET scan, no recurrent tumor could be proven yet clinically, by biopsy or during follow up. CONCLUSION 11C-choline PET is a feasible technique for evaluation of treatment for localized prostate cancer. The site of recurrence was detected correctly in 78% of the patients after external beam radiotherapy compared to 38% of the patients after radical prostatectomy. No positive PET scans were observed sofar in patients with a serum PSA <5ng/ml. Confirmatory studies and longer follow up are needed to determine the efficacy of 11C-choline PET compared to other imaging techniques.

Visualization of prostate cancer with 11C-choline positron emission tomography

BACKGROUND AND OBJECTIVE Visualization of prostate cancer with positron emission tomography (PET) using 2-[18F]-2-deoxy-D-glucose (FDG) as radiopharmaceutical is limited by the low uptake of FDG in the tumor and by radioactivity excreted into the bladder. More specific PET radiopharmaceuticals would be welcome. Carbon-11 labeled choline (CHOL) is a new radiopharmaceutical potentially useful for tumor imaging as it is incorporated in the cell membranes as phosphatidylcholine. We prospectively studied the visualization of prostate cancer using CHOL PET. METHODS A total of 25 consecutive patients with histologically proven prostate cancer and five patients with a benign prostate were included. PET images were performed with an ECAT HR(+) using 400MBq CHOL. Data acquisition was started at 5 minutes post-injection. Attenuation-corrected images were evaluated visually. Standardized uptake values (SUV) were calculated of the normal prostate gland and of the prostate tumor tissue. RESULTS The normal prostate was visualized with a mean SUV of 2.3 (range 1.3-3.2). The primary tumor could be visualized with a mean SUV of 5.0 (range 2.4-9.5). Lymph node metastases >5mm could be identified. Non-specific uptake of CHOL was noticed in the intestines. Little to no radioactivity in the bladder was observed. CONCLUSION Carbon-11-choline is avidly taken up in prostate cancer, both primary tumor and lymph node metastases, in the virtual absence of urinary radioactivity. These results confirm the early results obtained by others and permit further clinical research on the value of CHOL PET as a metabolic imaging technique in areas where conventional imaging have a limited sensitivity.

Strain-Promoted Copper-Free "Click" Chemistry for 18F Radiolabeling of Bombesin

Bombesin is a 14 amino acid (Pyr-Gln-Arg-Leu-Gly-AsnGln-Trp-Ala-Val-Gly-His-Leu-Met-NH2) neuropeptide, which binds with high affinity to the gastrin-releasing peptide receptor (GRPR). Bombesin has received much attention in the field of nuclear imaging because the GRPR is massively overexpressed on a variety of tumor cells, including breast and prostate tumor cells, thus making bombesin a promising radioligand for the diagnosis and imaging of cancer. Much effort has been invested in the development of labeled bombesin analogues. Bombesin is often modified in the form of Lys[3]-bombesin, which allows for site-selective introduction of the radionuclide at the terminal amino

Carbon-11 labelled tyrosine to study tumor metabolism by positron emission tomography (PET)

To measure the rate of protein synthesis in human neoplasms by positron emission tomography, we prepared no carrier added DL-(1-11C)-tyrosine by 11C-carboxylation of the appropriate α-lithioisocyanide followed by hydrolysis of the isocyanide function and removal of the protecting methoxy group. The purification, resolution and solvent switch to saline was performed by high performance liquid chromatography (HPLC). DL-(1-11C)-Tyrosine in 0.1 N NaH2PO4 buffer was prepared with a radiochemical yield of 8%–16% (EOS, 35 min). The enantiomeric separation and solvent switch to saline were achieved in 5 min and 10 min respectively. Consequently L-(1-11C)-tyrosine in physiological saline was obtained in 2%–4% radiochemical yield. Tumor accumulation in rats with the experimental WALKER 256 carcinosarcoma was observed for both the L- and D-isomer. Using positron emission tomography a tumor/muscle ratio of two was observed for the L-isomer 15 min after injection. The corresponding figure for the D-isomer was 2.5. The first clinical results with DL-(1-11C)-tyrosine show accumulation of radioactivity in meningioma, a primary breast carcinoma and in liver metastases of a colonic carcinoma.

Enhanced cerebral uptake of receptor ligands by modulation of P-glycoprotein function in the blood-brain barrier.

Low cerebral uptake of some therapeutic drugs can be enhanced by modulation of P‐glycoprotein (P‐gp), an ATP‐driven drug efflux pump at the blood–brain barrier (BBB). We investigated the possibility of increasing cerebral uptake of the β‐adrenergic ligands S‐1′‐[18F]‐fluorocarazolol (FCAR) and [11C]‐carazolol (CAR) in P‐gp knockout mice (mdr1a (−/−)) and by modulation of P‐gp with cyclosporin A (CsA) in rats. Specific and nonspecific binding of FCAR in the rat brain were doubled by CsA, while target/nontarget ratios and clearance from plasma (area under curve (AUC)) were not affected. Cerebral uptake of CAR in rats was much lower than FCAR and nonspecific. CsA increased this uptake 5–6‐fold, not only due to P‐gp modulation in the BBB but also to a 2‐fold higher plasma AUC. In the CNS of mdr1a (−/−) mice, uptake of FCAR and CAR was, respectively, 2‐fold and 3‐fold higher than in mdr1a (+/+) mice. These results indicate that the cerebral uptake of β‐adrenoceptor ligands can be increased by administration of P‐gp modulators such as CsA without affecting regional distribution in the brain. P‐gp modulation could improve the count statistics in PET studies of the CNS. Synapse 36:66–74, 2000.

An improved method for the preparation of [11C]verapamil

This paper describes an improved preparation of [11C]verapamil by reaction of [11C]methyl triflate with desmethylverapamil. The optimal reaction temperature, amount of precursor and reaction time were assessed. With this method [11C]verapamil can be prepared with a reproducible radiochemical yield of 66 +/- 4% (EOB, based on [11C]methyltriflate). Total synthesis time was 60 min. Radiochemical purity was >99% and specific activities varied between 5 and 30TBq/mmol.

UPTAKE OF RADIOLIGANDS BY RAT-HEART AND LUNG INVIVO - CGP-12177 DOES AND CGP-26505 DOES NOT REFLECT BINDING TO BETA-ADRENOCEPTORS

The biodistribution of (-)-4-(3-t-butylamino-2-hydroxypropoxy)-[5,7-3H-benzimidazol-2-one (CGP12177, a non-selective beta-adrenoceptor antagonist) and 1-[2-(3-carbamoyl-4-hydroxy)-(5-3H-phenoxy)]-2-propanol methanesulfonate, (CGP26505, a beta 1-adrenoceptor antagonist) was studied in rats pretreated with various alpha- and beta-adrenoceptor blocking drugs (5 min before 3H injection, in dosages at which the drugs demonstrated the expected selectivity). Cardiac and pulmonary radioactivity were measured after 10 min, when specific binding was maximal. Uptake of [3H]CGP12177 was linked to binding to beta-adrenoceptors since it was not affected by prazosin or yohimbine, and was equally well inhibited by propranolol, unlabelled CGP12177 and isoprenaline. Moreover, atenolol and CGP20712A inhibited [3H]CGP12177 uptake in heart (predominantly beta 1-adrenoceptors) more potently than ICI 118,551, while in lungs (predominantly beta 2-adrenoceptors) ICI 118,551 was more potent than atenolol or CGP20712A. In contrast, [3H]CGP26505 uptake in the target organs was equally effectively inhibited by propranolol and ICI 118,551, and significantly lowered by alpha-adrenoceptor antagonists. We conclude that [11C]CGP12177, but not [11C]CGP2605 will be suitable for positron emission tomography imaging of beta-adrenoceptors in animals.

Imaging the Folate Receptor on Cancer Cells with 99mTc-Etarfolatide: Properties, Clinical Use, and Future Potential of Folate Receptor Imaging

Folate receptor (FR) can be used as a therapeutic target because of its expression on different epithelial cancers, such as ovarian, non–small cell lung, endometrial, and breast cancer. Assessing FR expression in tumors may help to identify patients who can benefit from FR-targeted therapeutics, such as vintafolide and farletuzumab. Different methods exist to detect FR expression. Tissue sampling has limited clinical utility, mainly because it requires an invasive procedure. 99mTc-etarfolatide, a 99mTc-labeled folate conjugate, is in late-phase trials in Europe and the United States. It allows noninvasive, whole-body imaging of the FR. This review focuses on this FR-imaging agent and how it may be used to direct FR-targeted therapy.

A novel beta-adrenoceptor ligand for positron emission tomography: Evaluation in experimental animals

Myocardial and pulmonary beta-adrenoceptors can be imaged and quantified with the antagonist (S)-4-[3[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-b enzimidazol-2-[11C]-one (S-[11C]CGP-12177). The synthesis of this ligand (based on the reaction of a precursor with [11C]phosgene) is laborious and in many centers the final product has a low and variable specific activity. This prevents widespread use of S-[11C]CGP-12177 for studies in patients. We prepared S-[11C]CGP-12388, the isopropyl analogue of CGP-12177, by a reliable one-pot procedure and evaluated the radiopharmaceutical for beta-adrenoceptor imaging. Blocking experiments with subtype-selective beta-adrenergic drugs showed that myocardial and pulmonary uptake of S-[11C]CGP-12388 in anesthetized rats reflects ligand binding to beta1- and beta2-adrenoceptors. In this animal model, clearance, metabolism and tissue/plasma ratios of S-[11C]CGP-12388 were similar to those of S-[11C]CGP-12177. A [18F]fluoroisopropyl analogue of CGP-12177 showed less favorable characteristics. S-[11C]CGP-12388 was therefore selected for evaluation in humans and it may become the tracer of choice for clinical studies since it is easily prepared.

Synthesis and evaluation of radiolabeled antagonists for imaging of beta-adrenoceptors in the brain with PET

Five potent, lipophilic beta-adrenoceptor antagonists (carvedilol, pindolol, toliprolol and fluorinated analogs of bupranolol and penbutolol) were labeled with either carbon-11 or fluorine-18 and evaluated for cerebral beta-adrenoceptor imaging in experimental animals. The standard radioligand for autoradiography of beta-adrenoceptors, [125I]-iodocyanopindolol, was also included in this survey. All compounds showed either very low uptake in rat brain or a regional distribution that was not related to beta-adrenoceptors, whereas some ligands did display specific binding in heart and lungs. Apparently, the criteria of a high affinity and a moderately high lipophilicity were insufficient to predict the suitability of beta-adrenergic antagonists for visualization of beta-adrenoceptors in the central nervous system.