Targeted α-Emitter Therapy with 212Pb-DOTAMTATE for the Treatment of Metastatic SSTR-Expressing Neuroendocrine Tumors: First-in-Humans Dose-Escalation Clinical Trial.

Peptide receptor radiotherapy with somatostatin analogs has been successfully used for years as a treatment for somatostatin-overexpressing tumors. Treatment of neuroendocrine tumors (NETs) with the ß-particle emitter 177Lu-DOTATATE is currently considered the standard of care for subjects with gastroenteropancreatic NETs. Despite the success of 177Lu-DOTATATE, there remains significant room for improvement in terms of both safety and efficacy. Targeted α-emitter therapy with isotopes such as 212Pb has the potential to improve both. Here, we present the preliminary results of the phase 1 first-in-humans dose-escalation trial evaluating 212Pb-DOTAMTATE (a bifunctional metal chelator [DOTAM] and the SSTR-targeting peptide [TATE]) in patients with somatostatin receptor-positive NETs. Methods: Twenty subjects with histologically confirmed NETs, prior positive somatostatin analog scans, and no prior history of 177Lu/90Y/111In peptide receptor radiotherapy, with different primary sites of the disease, were enrolled. Treatment began with single ascending doses of 212Pb-DOTAMTATE, with subsequent cohorts receiving an incremental 30% dose increase, which was continued until a tumor response or a dose-limiting toxicity was observed. This was followed by a multiple ascending dose regimen. The recommended phase 2 dose regimen consisted of 4 cycles of 2.50 MBq/kg (67.6 µCi/kg) of 212Pb-DOTAMTATE administered at 8-wk intervals, intravenously. Results: Ten subjects received the highest dose, 2.50 MBq/kg/cycle (67.6 µCi/kg/cycle). Treatment was well tolerated, with the most common treatment-emergent adverse events being nausea, fatigue, and alopecia. No serious treatment-emergent adverse events were related to the study drug, and no subjects required treatment delay or a dose reduction. An objective radiologic response of 80% was observed for the first 10 subjects treated at the recommended phase 2 dose. Conclusion: Targeted α-therapy with 212Pb-DOTAMTATE has been shown to be well tolerated. Preliminary efficacy results are highly promising. If these results are confirmed in a larger, multicenter clinical trial, 212Pb-DOTAMTATE would provide a substantial benefit over currently Food and Drug Administration-approved therapies for patients with metastatic or inoperable SSTR-expressing NETs regardless of the grade and location of the primary tumor.

64Cu-DOTATATE PET/CT for Imaging Patients with Known or Suspected Somatostatin Receptor-Positive Neuroendocrine Tumors: Results of the First U.S. Prospective, Reader-Masked Clinical Trial.

Studies demonstrate that the investigational 64Cu-DOTATATE radiopharmaceutical may provide diagnostic and logistical benefits over available imaging agents for patients with somatostatin receptor (SSTR)-positive neuroendocrine tumors (NETs). Accordingly, we aimed to prospectively determine the lowest dose of 64Cu-DOTATATE that facilitates diagnostic-quality scans and evaluated the diagnostic performance and safety in a phase III study of patients with SSTR-expressing NETs. Methods: A dose-ranging study was conducted on 12 patients divided into 3 dose groups (111 MBq [3.0 mCi], 148 MBq [4.0 mCi], and 185 MBq [5.0 mCi] ± 10%) to determine the lowest dose of 64Cu-DOTATATE that produced diagnostic-quality PET/CT images. Using the 64Cu-DOTATATE dose identified in the dose-ranging study, 3 independent nuclear medicine physicians who were masked to all clinical information read PET/CT scans from 21 healthy volunteers and 42 NET-positive patients to determine those with disease or no disease, as well as those with localized versus metastatic status. Masked-reader evaluations were compared with a patient-specific standard of truth, which was established by an independent oncologist who used all previously available pathology, clinical, and conventional imaging data. Diagnostic performance calculated for 64Cu-DOTATATE included sensitivity, specificity, negative predictive value, positive predictive value, and accuracy. Inter- and intrareader reliability, as well as ability to differentiate between localized and metastatic disease, was also determined. Adverse events were recorded from 64Cu-DOTATATE injection through 48 h after injection. Results: The dose-ranging study identified 148 MBq (4.0 mCi) as the optimal dose to obtain diagnostic-quality PET/CT images. After database lock, diagnostic performance from an initial majority read of the 3 independent readers showed a significant 90.9% sensitivity (P = 0.0042) and 96.6% specificity (P < 0.0001) for detecting NETs, which translated to a 100.0% sensitivity and 96.8% specificity after correcting for an initial standard-of-truth misread. Excellent inter- and intrareader reliability, as well as ability to distinguish between localized and metastatic disease, was also noted. No adverse events were related to 64Cu-DOTATATE, and no serious adverse events were observed. Conclusion:64Cu-DOTATATE PET/CT is a safe imaging technique that provides high-quality and accurate images at a dose of 148 MBq (4.0 mCi) for the detection of somatostatin-expressing NETs.

Preclinical Investigation of 212Pb-DOTAMTATE for Peptide Receptor Radionuclide Therapy in a Neuroendocrine Tumor Model.

Somatostatin analogues have been examined as a treatment for somatostatin receptor overexpressing tumors for years; specifically, octreotate (TATE) and octreotide (TOC). Several versions of these analogues coupled to beta or gamma nuclides are currently used as imaging agents, as treatments with peptide receptor radionuclide therapy (PRRT) for patients with neuroendocrine tumors or are being explored in preclinical and clinical settings. Our study describes the use of 212Pb-DOTAMTATE, the octreotate analogue, in combination with 212Pb, the parent of an alpha emitter. Preclinical studies demonstrated tumor targeting of 212Pb-DOTAMTATE of >20% ID/g up to 24 hours post drug injection. The addition of kidney protection agents, including l-lysine and l-arginine decreases drug accumulation in the kidneys and the addition of ascorbic acid to the chelation mixture reduces oxidation of the drug product. 212Pb-DOTAMTATE displays a favorable toxicity profile with single-dose injections of 20 µCi showing 100% survival and with nontoxic cumulative doses up to 45 µCi, when fractionated into three smaller doses of 15 µCi. In an initial efficacy study, a single 10 µCi injection of 212Pb-DOTAMTATE extended the mean survival 2.4-fold. Efficacy was enhanced by giving three treatment cycles of 212Pb-DOTAMTATE and reducing the time between injections to two weeks. Efficacy was optimized further by the addition of a chemo-sensitizing agent, 5-fluorouracil, given in combination with three cycles of 10 µCi 212Pb-DOTAMTATE. These conditions led to 79% of the animals being tumor free at the end of the 31-week study suggesting that 212Pb-DOTAMTATE alone or in combination with a chemotherapeutic may have positive clinical implications.

Safety and Effectiveness of 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy After Regional Hepatic Embolization in Patients With Somatostatin-Expressing Neuroendocrine Tumors.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) with Lu-DOTATATE is shown to be an effective therapeutic option for somatostatin-expressing neuroendocrine neoplasms. Some concerns are raised over safety of this modality in patients with a history of regional chemoembolization and radionuclide hepatic embolization (CRHE) and is cause of reluctance among some physicians for suggesting Lu-DOTATATE in this patient population. METHODS: We retrospectively reviewed 143 patients with somatostatin-expressing neuroendocrine tumors who underwent Lu-DOTATATE PRRT. Statistical analysis was performed on effect of Lu-DOTATATE in patients with and without prior CRHE using resampling procedures and correlation coefficient (r). RESULTS: Proportion of toxicity in patients with and without CRHE was comparable (P = 0.246). No statistically significant correlation (r) found between any toxicity and prior CRHE (r = -0.3 to -0.03) or time elapsed between embolization and the first cycle of PRRT (r = -0.59 to 0.17). Following PRRT, 76.5% of patients with CRHE experienced benefit (partial response + stable disease), whereas 23.4% experienced progressive disease. Patients with CRHE showed more stable disease (P = 0.048) and less progressive disease (P = 0.046) following PRRT compared with no CRHE. The CRHE and no-CRHE status shared same probability for developing partial response/complete response following PRRT (P = 0.50). CONCLUSIONS: Treatment with Lu-DOTATATE did not show clinically or statistically significant toxicity in CRHE patients regardless of frequency of embolization or time interval between embolization and first PRRT. Results suggested a statistically significant higher response rate in patients with a history of CRHE. A prior history of CRHE is not a contraindication to subsequent PRRT.

Peptide Receptor Radionuclide Therapy With 177Lu-Octreotate in Patients With Somatostatin Receptor Expressing Neuroendocrine Tumors: Six Years' Assessment.

OBJECTIVES: Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is a promising treatment for patients with inoperable, well to moderately differentiated metastatic neuroendocrine tumors (NETs). In continuation of our novel study with the radionuclide lutetium Lu, we now present further results of Lu DOTATATE therapy in managing NETs and other somatostatin receptor-expressing tumors in a larger and more diverse patient group. PATIENTS AND METHODS: One hundred forty-four consecutive patients (85 men and 59 women; age range, 11-87 years; mean age, 58.5 years) with histologically confirmed NET were enrolled. One hundred forty-three patients received at least 1 cycle of treatment. Among them, 132 were deemed evaluable by having at least 1 cycle of treatment and a posttreatment MRI or CT scan for assessment based on modified Response Evaluation Criteria in Solid Tumors. Response to therapy was evaluated in terms of progression-free survival, overall survival, as well as radiologic, biochemical, and clinical responses. Further, analysis of symptoms was reviewed during therapy and also in subsequent follow-ups for safety evaluation. Renal, gastrointestinal (GI), hepatic, and hematological adverse events were evaluated using National Cancer Institute common toxicities criteria V4.03, through full blood panels, as well as consultation with patients for any symptoms and/or adverse events. RESULTS: As of July 2016, median progression-free survival was about to be reached. Of 28 patients who have completed Lu DOTATATE therapy (completion of 4 or more cycles of treatment and all designated follow-ups), no patient showed complete response (CR), 8 patients (28.57%) showed partial response (PR), 16 patients (57.14%) showed stable disease (SD), and progressive disease (PD) was observed in 4 patients (14.28%). The objective response rate (CR + PR) of this group was 28.57% (n = 8) with a cumulative disease control (CR + PR + SD) of 85.71% (n = 24).Among 132 evaluable patients, assessment of treatment response using modified Response Evaluation Criteria in Solid Tumors criteria revealed CR in none of the patients, PR in 12 patients (9.09%), SD in 66 patients (50%), whereas PD, which included patients who passed away, was observed in 54 patients (40.90%), yielding an objective response rate of 9.09% (n = 12) and a cumulative disease control rate of 59.09% (n = 78).Symptoms including abdominal pain, diarrhea, flushing, and fatigue improved in over 50% of the patients, whereas weight loss improved in 28.26% of the patients. No grade 3 or grade 4 renal toxicities were found, though eleven grade 3 and five grade 4 hematological as well as three grade 3 hepatotoxicities were reported. Grade 3 hematotoxicity lasted an average of 2.7 months, and grade 4 lasted for only 0.9 months, whereas grade 3 hepatotoxicity lasted an average of 3.1 months. CONCLUSIONS: Lu-octreotate peptide receptor radionuclide therapy has shown promising potential as a safe and effective targeted therapy in inoperable, well to moderately differentiated metastatic neuroendocrine cancers. The results of the multicenter randomized clinical trial conducted in United States and Europe are concordant with current study.

Radiolabeling of DOTA-like conjugated peptides with generator-produced (68)Ga and using NaCl-based cationic elution method.

Gallium-68 ((68)Ga) is a generator-produced radionuclide with a short half-life (t½ = 68 min) that is particularly well suited for molecular imaging by positron emission tomography (PET). Methods have been developed to synthesize (68)Ga-labeled imaging agents possessing certain drawbacks, such as longer synthesis time because of a required final purification step, the use of organic solvents or concentrated hydrochloric acid (HCl). In our manuscript, we provide a detailed protocol for the use of an advantageous sodium chloride (NaCl)-based method for radiolabeling of chelator-modified peptides for molecular imaging. By working in a lead-shielded hot-cell system,(68)Ga(3+) of the generator eluate is trapped on a cation exchanger cartridge (100 mg, ∼8 mm long and 5 mm diameter) and then eluted with acidified 5 M NaCl solution directly into a sodium acetate-buffered solution containing a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or DOTA-like chelator-modified peptide. The main advantages of this procedure are the high efficiency and the absence of organic solvents. It can be applied to a variety of peptides, which are stable in 1 M NaCl solution at a pH value of 3-4 during reaction. After labeling, neutralization, sterile filtration and quality control (instant thin-layer chromatography (iTLC), HPLC and pH), the radiopharmaceutical can be directly administered to patients, without determination of organic solvents, which reduces the overall synthesis-to-release time. This procedure has been adapted easily to automated synthesis modules, which leads to a rapid preparation of (68)Ga radiopharmaceuticals (12-16 min).

Radiosynthesis of clinical doses of 68Ga-DOTATATE (GalioMedix™) and validation of organic-matrix-based 68Ge/68Ga generators.

INTRODUCTION: 68Ga-DOTATATE is a radiolabeled peptide-based agonist that targets somatostatin receptors overexpressed in neuroendocrine tumors. Here, we present our results on validation of organic matrix 68Ge/68Ga generators (ITG GmbH) applied for radiosynthesis of the clinical doses of 68Ga-DOTATATE (GalioMedixTM). METHODS: The clinical grade of DOTATATE (25 µg±5 µg) compounded in 1 M NaOAc at pH=5.5 was labeled manually with 514±218 MBq (13.89±5.9 mCi) of 68Ga eluate in 0.05 N HCl at 95°C for 10 min. The radiochemical purity of the final dose was validated using radio-TLC. The quality control of clinical doses included tests of their osmolarity, endotoxin level, radionuclide identity, filter integrity, pH, sterility and 68Ge breakthrough. RESULTS: The final dose of 272±126 MBq (7.35±3.4 mCi) of 68Ga-DOTATATE was produced with a radiochemical yield (RCY) of 99%±1%. The total time required for completion of radiolabeling and quality control averaged approximately 35 min. This resulted in delivery of 50%±7% of 68Ga-DOTATATE at the time of calibration (not decay corrected). CONCLUSIONS: 68Ga eluted from the generator was directly applied for labeling of DOTA-peptide with no additional pre-concentration or pre-purification of isotope. The low acidity of 68Ga eluate allows for facile synthesis of clinical doses with radiochemical and radionuclide purity higher than 98% and average activity of 272±126 MBq (7.3±3 mCi). There is no need for post-labeling C18 Sep-Pak purification of final doses of radiotracer. Advances in knowledge and implications for patient care. The clinical interest in validation of 68Galabeled agents has increased in the past years due to availability of generators from different vendors (Eckert-Ziegler, ITG, iThemba), favorable approach of U.S. FDA agency to initiate clinical trials, and collaboration of U.S. centers with leading EU clinical sites. The list of 68Ga-labeled tracers evaluated in clinical studies should growth because of the sensitivity of PET technique, the simplicity of the shakebake approach for the dose preparation and reliability of 68Ge/68Ga generators. Our studies have confirmed the reproducible elution profile, and high reliability of ITG GmbH generators required for routine doses preparation according to FDA recommendations.

Assessment of vulnerable atherosclerotic and fibrotic plaques in coronary arteries using (68)Ga-DOTATATE PET/CT.

Activated macrophages which express somatostatin receptor-2 (SSTR-2) play a vital role in rupture of the vulnerable atherosclerotic plaques, which result in death. (68)Ga-DOTATATE binds to somatostatin receptors 2, and therefore, can serve as potential radiotracer to detect atherosclerotic plaques. The purpose of this study was to generate preliminary data with this agent in vulnerable or fibrotic atherosclerotic plaques in the coronary arteries. We evaluated a total of 44 patients with neuroendocrine tumors (NET) who underwent (68)Ga-DOTATATE PET/CT. In each subject, 7 segments in the coronary arteries were assessed, maximum SUV values and target-to-background ratios (TBRs) were calculated. The lesions detected by CT (a total of 308) were divided into 3 groups based on the Hounsfield unites (HU), and of which, 131 with HU less than 70 were classified as being normal (Control Group), 129 with HU 71-188 as fibrotic plaques (Group 2), and. 48 lesions with HU more than 188 as atherosclerotic plaques (Group 3). The mean TBR value in the normal group was 1.345 ± 0.58 while the mean TBR value in the fibrotic plaque group was 1.752 ± 1.50 (p 0.0043) and in atherosclerotic plaques group was (2.043 ± 1.76, p<0.0001). There was a significant correlation (p=0.0026) between (68)Ga-DOTATATE uptake and the progression to formation of atherosclerotic plaques, based on HU. In patients with neuroendocrine tumors, (68)Ga-DOTATATE PET/CT showed significantly increased uptake in the fibrotic and vulnerable atherosclerotic plaques compared to normal coronary arteries suggesting a potential role of this tracer for molecular assessment of coronary artery disease in this population.

The value of (68)Ga-DOTATATE PET/CT in diagnosis and management of neuroendocrine tumors compared to current FDA approved imaging modalities: a review of literature.

Neuroendocrine tumors (NETs) are rare group of neoplasms arising from nervous and endocrine systems. Somatostatin analogue imaging is a functional imaging modality of choice for evaluating the NETs. Recent availability of positron emitting radioisotope labeled somatostatin analogues to image neuroendocrine cancers, has raised the interests to use this new imaging modality in management of patients with NETs. (68)Ga-DOTATATE PET/CT has demonstrated superiority in lesion detection compared to Octreoscan, MIBG scintigraphy and MRI. In this article, we reviewed the published studies evaluating the role of (68)Ga-DOTATATE PET in diagnosis and management of patients with neuroendocrine tumors and comparing it to current FDA approved imaging modalities including Octreoscan, MIBG scintigraphy, (18)F FDG PET/CT, CT and MRI.

Detection of canonical hedgehog signaling in breast cancer by 131-iodine-labeled derivatives of the sonic hedgehog protein.

Activation of hedgehog (HH) pathway signaling is observed in many tumors. Due to a feedback loop, the HH receptor Patched (PTCH-1) is overexpressed in tumors with activated HH signaling. Therefore, we sought to radiolabel the PTCH-1 ligand sonic (SHH) for detection of cancer cells with canonical HH activity. Receptor binding of ¹³¹I-SHH was increased in cell lines with high HH pathway activation. Our findings also show that PTCH-1 receptor expression is decreased upon treatment with HH signaling inhibitors, and receptor binding of ¹³¹I-SHH is significantly decreased following treatment with cyclopamine. In vivo imaging and biodistribution studies revealed significant accumulation of ¹³¹I-SHH within tumor tissue as compared to normal organs. Tumor-to-muscle ratios were approximately 8 : 1 at 5 hours, while tumor to blood and tumor to bone were 2 : 1 and 5 : 1, respectively. Significant uptake was also observed in liver and gastrointestinal tissue. These studies show that ¹³¹I-SHH is capable of in vivo detection of breast tumors with high HH signaling. We further demonstrate that the hedgehog receptor PTCH-1 is downregulated upon treatment with hedgehog inhibitors. Our data suggests that radiolabeled SHH derivatives may provide a method to determine response to SHH-targeted therapies.

Base pairing within the psi32,psi39-modified anticodon arm of Escherichia coli tRNA(Phe).

The base-base hydrogen bond interactions of the psi32,psi39-modified anticodon arm of Escherichia coli tRNAPhe have been investigated using heteronuclear NMR spectroscopy. psi32 and psi39 were enzymatically introduced into a [13C,15N]-isotopically enriched RNA sequence corresponding to the tRNAPhe anticodon arm. Both the psi32-A38 and A31-psi39 nucleotide pairs form Watson-Crick base pairing schemes and the anticodon nucleotides adopt a triloop conformation. Similar effects were observed previously with D2-isopentenyl modification of the A37 N6 that also is native to the tRNAPhe anticodon arm. These results demonstrate that the individual modifications are not sufficient to produce the 32-38 bifurcated hydrogen bond or the U-turn motifs that are observed in crystal structures of tRNAs and tRNA-protein complexes. Thus the formation of these conserved structural features in solution likely require the synergistic interaction of multiple modifications.

Accurate measurement of 15N-13C residual dipolar couplings in nucleic acids.

New 3D HCN quantitative J (QJ) pulse schemes are presented for the precise and accurate measurement of one-bond 15N1/9-13C1', 15N1/9-13C6/8, and 15N1/9-13C2/4 residual dipolar couplings (RDCs) in weakly aligned nucleic acids. The methods employ 1H-13C multiple quantum (MQ) coherence or TROSY-type pulse sequences for optimal resolution and sensitivity. RDCs are obtained from the intensity ratio of H1'-C1'-N1/9 (MQ-HCN-QJ) or H6/8-C6/8-N1/9 (TROSY-HCN-QJ) correlations in two interleaved 3D NMR spectra, with dephasing intervals of zero (reference spectrum) and approximately 1/(2J(NC)) (attenuated spectrum). The different types of 15N-13C couplings can be obtained by using either the 3D MQ-HCN-QJ or TROSY-HCN-QJ pulse scheme, with the appropriate setting of the duration of the constant-time 15N evolution period and the offset of two frequency-selective 13C pulses. The methods are demonstrated for a uniformly 13C, 15N-enriched 24-nucleotide stem-loop RNA sequence, helix-35psi, aligned in the magnetic field using phage Pf1. For measurements of RDCs systematic errors are found to be negligible, and experiments performed on a 1.5 mM helix-35psi sample result in an estimated precision of ca. 0.07 Hz for 1D(NC), indicating the utility of the measured RDCs in structure validation and refinement. Indeed, for a complete set of 15N1/9-13C1', 15N1/9-13C6/8, and 15N1/9-13C2/4 dipolar couplings obtained for the stem nucleotides, the measured RDCs are in excellent agreement with those predicted for an NMR structure of helix-35psi, refined using independently measured observables, including 13C-1H, 13C-13C and 1H-1H dipolar couplings.

Synthesis of phosphorofluoridates and phosphorofluoridothioates via the phosphoramidite approach.

We present a very efficient synthetic procedure leading to the phosphorofluoridates RO-P(O)(OH)F 1 or phosphorofluoridothioates RO-P(S)(OH)F 2, which is based on the intermediary of fluorophosphoramidites (RO)P(F)N(i)Pr2 5 [R = 9-(hydroxyethyloxymethyl)guaninyl), 3'azido-3'deoxythymidinyl, thymidinyl, anhydrothymidinyl, cholesteryl, N6-benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyadenosinyl]. The activation of the amino group was performed with trimethylchlorosilane (TMCS).

Metal ion stabilization of the U-turn of the A37 N6-dimethylallyl-modified anticodon stem-loop of Escherichia coli tRNAPhe.

Nucleoside base modifications can alter the structures, dynamics, and metal ion binding properties of transfer RNA molecules and are important for accurate aminoacylation and for maintaining translational fidelity and efficiency. The unmodified anticodon stem-loop from Escherichia coli tRNA(Phe) forms a trinucleotide loop in solution, but Mg(2+) and dimethylallyl modification of A(37) N6 disrupt the loop conformation and increase the mobility of the loop and loop-proximal nucleotides. We have used NMR spectroscopy to investigate the binding and structural effects of multivalent cations on the unmodified and dimethylallyl-modified anticodon stem-loops from E. coli tRNA(Phe). The divalent cation binding sites were probed using Mn(2+) and Co(NH(3))(6)(3+). These ions bind along the major groove of the stem and associate with the anticodon loop on the major groove side in a nonspecific manner. Co(NH(3))(6)(3+) stabilizes the U-turn conformation of the loop in the dimethylallyl-modified molecule, and the chemical shift changes that accompany Co(NH(3))(6)(3+) binding are similar to those observed with the addition of Mg(2+). The base-phosphate and base-2'-OH hydrogen bonds that characterize the UNR U-turn motif lead to spectral signatures in the form of unusual (15)N and (1)H chemical shifts and reduced solvent exchange of the U(33) 2'-OH and N3H protons. The unmodified molecule also displays spectral features of the U-turn fold in the presence of Co(NH(3))(6)(3+), but the loop has additional conformations and is dynamic. The results indicate that charge neutralization by a polyvalent cation is sufficient to promote formation of the U-turn fold. However, base modification is necessary to destabilize competing alternative conformers even for a purine-rich loop sequence that is predicted to have strongly favorable base stacking energy.

Synthesis of Tri- and Tetracoordinate Phosphorus Compounds Containing a PCF3 Group by Nucleophilic Trifluoromethylation of the Corresponding PF Compounds.

A new way of forming P-C bonds: Catalytic amounts of F- ions facilitate the reaction of PIII -F compounds with CF3 SiMe3 to give PIII -CF3 compounds. These compounds can also be obtained in a one-pot procedure from PIII -OAr precursors (also shown).